Review: Mitochondria: in Sickness and in Health

Leading Edge
Review
Mitochondria: In Sickness and in Health

Jodi Nunnari1,* and Anu Suomalainen2,3,*
1Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
2Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland
3Department of Neurology, Helsinki University Central Hospital, 00290 Helsinki, Finland
*Correspondence: [email protected] (J.N.), [email protected] (A.S.)

DOI 10.1016/j.cell.2012.02.035
Mitochondria perform diverse yet interconnected functions, producing ATP and many biosynthetic
intermediates while also contributing to cellular stress responses such as autophagy and
apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated
with other cellular compartments. In addition, mitochondrial functions extend beyond the bound-
aries of the cell and influence an organism’s physiology by regulating communication between cells
and tissues. It is therefore not surprising that mitochondrial dysfunction has emerged as a key
factor in a myriad of diseases, including neurodegenerative and metabolic disorders. We provide
a current view of how mitochondrial functions impinge on health and disease.
Introduction ancestry of mitochondria and bacteriophage-related mtDNA

Mitochondria arose from an alpha-proteobacterium engulfed by maintenance systems make the organelle susceptible to antimi-
a eukaryotic progenitor (Lane and Martin, 2010). Like their bacte- crobial drugs: for example, mitochondrial translation is targeted
rial ancestor, mitochondria are comprised of two separate and by common antibiotics that block microbial ribosomes (amino-
functionally distinct outer (OMs) and inner membranes (IMs) glycosides, tetracyclines) (Hutchin et al., 1993; van den Bogert
that encapsulate the intermembrane space (IMS) and matrix and Kroon, 1981), and mtDNA maintenance is affected by anti-
compartments. They also contain a circular genome, mitochon- viral nucleoside analogs (Arnaudo et al., 1991). The genetic risk
drial DNA (mtDNA), that has been reduced during evolution factors underlying drug sensitivity of mitochondrial function are
through gene transfer to the nucleus. mtDNA is organized into expected to be numerous, but challenging to identify.
discrete nucleoids in the matrix. Interestingly, the closest The considerable resources a cell must provide to maintain the
relatives of many mtDNA-modifying enzymes, such as mtDNA mitochondrial compartment underscores the varied essential
polymerase, are bacteriophage proteins (Lecrenier et al., 1997; roles it plays. This is further demonstrated by the fact that mito-
Tiranti et al., 1997), suggesting that an infection of the mitochon- chondrial dysfunction is associated with an increasingly large
drial ancestor contributed to the development of mtDNA mainte- proportion of human inherited disorders and is implicated
nance machinery. In animals, mtDNA inheritance is almost in common diseases, such as neurodegenerative disorders,
exclusively maternal, and paternal mtDNA is actively destroyed cardiomyopathies, metabolic syndrome, cancer, and obesity.
in many species immediately after fertilization (Al Rawi et al., Below we review new developments in mitochondrial biology
2011; Sato and Sato, 2011). and discuss their relevance for human disease.
Advances in proteomic, genomic, and bioinformatic ap-
proaches have provided a comprehensive inventory of mito- Mitochondrial Defects Cause Diverse and Complex
chondrial proteins in various eukaryotes (Gaston et al., 2009; Human Diseases
Mootha et al., 2003; Pagliarini et al., 2008; Sickmann et al., Human mitochondrial disorders are a genetically heterogeneous
2003). This inventory indicates that mammalian mitochondria group of different diseases, caused by mutations in mitochon-
contain over 1,500 proteins, which vary in a tissue-dependent drial and/or nuclear DNA, which encompass almost all fields of
manner. Because mtDNA encodes only 13 of these proteins, medicine (Ylikallio and Suomalainen, 2012). Mitochondrial
mitochondria depend on the nucleus and other cellular compart- diseases can affect any organ system, manifest at any age,
ments for most of their proteins and lipids. Nuclear-encoded and, depending on where the gene defect lies, be inherited
mitochondrial proteins are actively imported and sorted into from an autosome, the X chromosome, or maternally. Currently,
each mitochondrial compartment (Neupert and Herrmann, mitochondrial disorders cannot be cured, and available treat-
2007; Schmidt et al., 2010), followed by coordinated assembly ments are directed at relieving symptoms (Suomalainen, 2011).
into macromolecular complexes, comprised of subunits en- Mitochondrial diseases display both clinical heterogeneity and
coded by nuclear and mitochondrial DNA. have tissue-specific manifestations, as indicated by the fact that
Although mammalian mitochondria have retained some mutations in the same mitochondrial protein complex lead to
bacterial features, it is estimated that only a small percentage disparate disease phenotypes. For example, defects in respira-
of human mitochondria are derived from the original endosym- tory complex I can lead to atrophy of the optic nerve in adults
biont (Gabaldón and Huynen, 2004). However, the bacterial (Wallace et al., 1988) or subacute necrotizing encephalopathy
Cell 148, March 16, 2012 ª2012 Elsevier Inc. 1145

in infants (Morris et al., 1996). The most common nuclear muta- electrons to the IM-localized electron transport chain (ETC).
tions associated with mitochondrial diseases are found in the The ETC consists of four protein machines (I–IV), which through
gene encoding mitochondrial DNA polymerase g and can mani- sequential redox reactions undergo conformational changes to
fest as early-onset hepatocerebral disorder, juvenile cata- pump protons from the matrix into the IMS. The first and largest
strophic epilepsy, or adult-onset ataxia-neuropathy syndrome of the respiratory complexes, complex I, is a sophisticated
(Euro et al., 2011; Hakonen et al., 2005; Naviaux et al., 1999; microscale pump consisting of 45 core subunits, whose biogen-
Van Goethem et al., 2001). Another example of clinical variability esis requires an army of assembly factors (Diaz et al., 2011;
is exhibited by the recently characterized disease group linked to Efremov and Sazanov, 2011). The proton gradient generated
defects in mitochondrial aminoacyl-transfer RNA (tRNA) synthe- by complexes I, III, and IV is released through the rotary
tases (ARS2s), whose known essential function is to join a mito- turbine-like ATP synthase machine or complex V, which drives
chondrial tRNA with its cognate amino acid to be transfered phosphorylation of ADP to ATP (Okuno et al., 2011; Stock
to the ribosome for protein synthesis. ARS2 defects promote et al., 1999). Beyond ATP production, the inner-membrane elec-
a variety of phenotypes, including cardiomyopathies, cerebral trochemical potential generated by OXPHOS is a vital feature of
white matter disease, ovarial dysfunction, and hearing loss. the organelle (Mitchell, 1961). Membrane potential is harnessed
(Scheper et al., 2007; Götz et al., 2011; Pierce et al., 2011) The for other essential mitochondrial functions, such as mitochon-
nature of the molecular defect can often explain variations in drial protein import (Neupert and Herrmann, 2007), and is used
the severity and age-of-onset of these diseases, but not the vari- to trigger changes on the molecular level that alter mitochondrial
ability in tissue-specific manifestations, which may instead be behaviors in response to mitochondrial dysfunction.
defined by a patient’s complement of protective and risk alleles. Complexes I and III also generate reactive oxygen species
Phenotypic variability associated with mtDNA-linked diseases (ROS), including oxygen radicals and hydrogen peroxide, which
is also due, in part, to the high copy number of mtDNA in can damage key components of cells, including lipids, nucleic
mammalian cells, which can consequently contain both mutant acids, and proteins (Muller et al., 2004; Murphy, 2009). ROS
and wild-type mtDNAs populations—a situation called hetero- has been suggested to contribute to diseases associated with
plasmy (Holt et al., 1988). While mtDNA mutations in tRNA genes mitochondrial dysfunction, including neurodegeneration. For
possess high clinical variability not explained by heteroplasmy, example, Leber’s hereditary optic neuropathy is associated
in the case of protein-coding gene mutations, the degree of het- with mutations that alter the ubiquinone binding pocket of
eroplasmy correlates with the severity of phenotypes. For mtDNA-encoded complex I subunits (Pätsi et al., 2008) that likely
example, for the T8993C/G mutation of mtDNA, affecting affect electron delivery from the FeS centers of complex I to
ATPase6, a low mutant load causes pigment retinopathy, ataxia, ubiquinone, leading to an overreduction of FeS clusters, electron
and neuropathy in adults, whereas a high mutant load causes leak, and oxygen radical production.
maternally inherited Leigh syndrome in infants (Holt et al., Multiple lines of evidence indicate that mitochondrial ROS
1990; Tatuch et al., 1992). also influence homeostatic signaling pathways to control cell
Heteroplasmy can be affected by segregation of mtDNA and proliferation and differentiation and to contribute to adaptive
by selective mitochondrial degradative pathways. Examples of stress signaling pathways, such as hypoxia (Hamanaka and
nonrandom segregation include the nonrandom segregation of Chandel, 2010). Observations from premature aging mouse
neutral mtDNA variants in mice (Battersby et al., 2005; Jokinen models suggest that hematopoietic progenitors are especially
et al., 2010), and, in humans, the A3243G tRNALeu(UUR) mutation, sensitive to ROS and/or redox state changes that promote
whose load decreases in blood over years (Rahman et al., 2001). proliferation and prevent quiescence (Ito et al., 2004; Narasim-
In mice, cells with allogenic mtDNA are recognized and targeted haiah et al., 2005). Interestingly, progeroid mtDNA Mutator
by the innate immune system, indicating that mitochondrial mice, which accumulate mtDNA mutations, are severely anemic
DNA-dependent antigen presentation may play a role in mtDNA (Chen et al., 2009; Kujoth et al., 2005; Norddahl et al., 2011;
selection (Ishikawa et al., 2010). Selection of mtDNA may also Trifunovic et al., 2004) and have an early somatic stem cell
occur during oogenesis: in mice, mtDNA mutations in protein- dysfunction suppressed by n-acetyl-l-cysteine treatment. These
coding genes are underrepresented in offspring, suggesting observations imply that ROS/redox signaling affects somatic
a mechanism that selectively eliminates cells or organelles with stem cell function and causes progeroid symptoms (Ahlqvist
the most severe mutations (Fan et al., 2008; Stewart et al., et al., 2012) and that mitochondrial dysfunction in somatic
2008). Surprisingly, the fundamental molecular mechanisms stem cells may contribute to aging-related degeneration.
underlying the process of mtDNA distribution in cells and its In all cell types, mitochondria are the major cellular source of
tissue specificity are poorly understood, given that an under- NADH and house parts of the pyrimidine and lipid biosynthetic
standing of how the nucleoid is regulated is crucial to under- pathways, including the fatty acid b-oxidation pathway, which
standing mitochondrial diseases. converts long chain fatty acids to Acyl-CoA. Mitochondria also
regulate cellular levels of metabolites, amino acids, and cofac-
Mitochondria Are Metabolic Signaling Centers tors for various regulatory enzymes, including chromatin-modi-
The diverse nature of mitochondrial diseases highlights the many fying histone deacetylases. Moreover, mitochondria play
roles mitochondria play in cells and tissues. Mitochondria are a central role in metal metabolism, synthesizing heme and
best known for producing ATP via oxidative phosphorylation Fe-S clusters (Lill and Mühlenhoff, 2008), which are essential
(OXPHOS). In the matrix, tricarboxylic acid cycle (TCA) enzymes components of the major oxygen carrier, hemoglobin, as well
generate electron carriers (NADH and FADH2), which donate as OXPHOS and DNA repair machinery. Mitochondria also
1146 Cell 148, March 16, 2012 ª2012 Elsevier Inc.

Figure 1. Nutrient Sensors in Fasting and
Their Roles in Mitochondrial Disease
Both fasting and mitochondrial disease can
modify NAD+:NADH and AMP:ATP ratios through
decreased nutrient availability or through reduced
respiratory chain activity and have the potential to
activate (red) nutrient sensors Sirtuin 1 (Sirt, an
NAD+-dependent histone deacetylase) or AMP-
activated kinase (AMPK) and increase mito-
chondrial biogenesis by activating peroxisome
proliferator-activated receptor gamma coactivator
1-alpha (PGC-1alpha). Upon decreased utilization
of acetyl-coenzyme A (acetyl-coA), GCN5 (lysine
acetyltransferase 2A) is activated and acetylates
PGC1alpha, to inactivate it (blue). NAD+, nicotin-
amide adenine dinucleotide, oxidized form; NADH,
nicotinamide adenine dinucleotide, reduced form;
AMP, adenosine monophosphate; ATP, adeno-
sine triphosphate; Ac, acetyl group.
participate in Ca2+ homeostasis, shaping the spatiotemporal and increased ADP concentrations, both of which accompany
distribution of this second messenger by buffering Ca2+ flux a decrease in caloric intake or an increase in energy expenditure
from the plasma membrane and endoplasmic reticulum (ER) (Hardie et al., 2011; Mihaylova and Shaw, 2011). Through the
(Baughman et al., 2011; De Stefani et al., 2011). phosphorylation of a variety of targets, it upregulates catabolic
In neurons, the ability of mitochondria to modulate Ca2+ flux is pathways including gluconeogenesis, OXPHOS, and autophagy,
essential for controlling neurotransmitter release, neurogenesis, while inhibiting anabolic pathways including cell growth and
and neuronal plasticity. In addition, mitochondria supply copious proliferation (Cantó et al., 2010; Carling et al., 2011). Sirt1
amounts of ATP as well as the TCA intermediates that serve as responds to elevated levels of NAD+ that occur upon starvation
the building blocks for synthesis of GABA and glutamate neuro- and, together with AMPK, coordinately regulates mitochondrial
transmitters (Sibson et al., 1998; Waagepetersen et al., 2001). mass, nutrient oxidation, and ATP production to fit a cell’s partic-
Compromised oxidative metabolism may therefore alter neuro- ular needs via the transcription cofactor, peroxisome prolifera-
transmitter levels and render the brain uniquely sensitive to tor-activated receptor gamma coactivator 1 alpha (PGC-1a)
oxidative energetic deficits, as has been shown for pyruvate (Cantó et al., 2009, 2010; Jäger et al., 2007; Jeninga et al.,
carboxylase deficiency (Perry et al., 1985). Mitochondria- 2010; Puigserver et al., 1998; Wu et al., 1999).
mediated lipid synthesis is also critical for neuronal function, Nutrient responses are likely to be highly tissue specific. In the
as defects in lipoic acid synthase cause severe neonatal- liver, low blood lipid levels induce the nuclear PPAR-alpha
onset epilepsy (Mayr et al., 2011). These additional metabolic receptor, which ultimately induces ketogenesis. In adipose
functions of mitochondria depend, either directly or indirectly, tissue, mitochondria-derived starvation responses trigger lipol-
on OXPHOS, and thus can be secondarily affected by changes ysis to provide peripheral tissues with fuels (Kharitonenkov
in respiration and respiratory complex deficiency. et al., 2005; Nishimura et al., 2000). In the hypothalamus, AMPK
affects neuronal plasticity and transmitter receptor activity to
Mitochondria as Energy Sensors and Beacons promote food intake and provide neuronal protection in response
The central roles of mitochondria in metabolism position them as to hunger (Kuramoto et al., 2007; Yang et al., 2011). During a high
key actors in global energy modulation. An increased need for nutritional load, multiple cell types exhibit high levels of ATP and
ATP is met by increasing mitochondrial mass and inducing NADH levels and the metabolic balance tips toward lipid and
OXPHOS. For example, an increase of mitochondrial mass and glycogen storage, and mitochondrial biogenesis is downregu-
activity is observed after endurance exercise (Hoppeler and lated, increasing glycolytic ATP synthesis.
Fluck, 2003). The regulation of mitochondrial biogenesis is tightly How does the interrelationship between nutrient sensing and
coordinated with pathways that induce vascularization, enhance mitochondrial function contribute to disease? Not surprisingly,
oxygen delivery to tissues, and enable oxygen supply to facilitate alterations in mitochondrial mass and activity are contributory
efficient mitochondrial oxidization of glucose and fat (Arany factors in obesity and metabolic syndrome. Comparisons
et al., 2008). between identical twin pairs discordant for obesity revealed
Mitochondrial metabolism is both the basis for and target of significantly reduced mtDNA levels and decreased mitochon-
nutrient signals that ultimately orchestrate an integrated physio- drial mass in the obese twin’s adipose tissue, despite identical
logical response. The molecular components that sense energy mtDNA sequences (Pietiläinen et al., 2008). This observation
status include transcription factors, hormones, cofactors, indicates the importance of environmental effects in regulating
nuclear receptors, and kinases, which detect specific signals mitochondrial mass and biogenesis. The discovery of active
of mitochondrial activity, such as the NAD+:NADH ratio, the brown adipose tissue in adult humans has opened up an
AMP:ATP ratio, or acetyl-CoA levels (Figure 1). intriguing avenue in obesity research by clarifying the role of
Two key cellular sensors of metabolic status are the AMP-acti- adaptive thermogenesis in counteracting fat storage through
vated protein kinase (AMPK) and Sirt1, an NAD+-dependent UCP1-mediated mitochondrial uncoupling (van Marken Lichten-
deacetylase. AMPK is activated by an increase in AMP:ATP ratio belt et al., 2009; Virtanen et al., 2009).

Studies of the Deletor mouse provide a model to interrogate tionally and functionally distinct regions (Reichert and Neupert,
the physiological changes associated with late-onset mitochon- 2002): the inner boundary region is in close apposition to the
drial disease (Tyynismaa et al., 2005). Even when these animals OM and facilitates lipid trafficking, mitochondrial protein import,
receive normal nutrition, their muscle cells misinterpret an and respiratory complex assembly, the cristae are invaginations
OXPHOS defect and decreased ATP synthesis as starvation. that penetrate into the matrix and house assembled respiratory
Interestingly, a key regulator of anabolic processes, Akt kinase, complexes and are thought to increase the local charge
is also activated under these conditions (Tyynismaa et al., density/pH to enhance ATP synthesis via OXPHOS (Strauss
2010). In these mice, induction of mitochondrial biogenesis by et al., 2008; Perkins and Frey, 2000); and crista junctions are
high-fat feeding appears to be beneficial by inducing mitochon- tubules that connect the cristae to the boundary and segregate
drial mass and OXPHOS activity (Ahola-Erkkilä et al., 2010). The soluble intermembrane space components from the boundary
progressive disease course of mice with cytochrome c oxidase regions. These junctions are restructured during apoptosis to
deficiencies can similarly be delayed with treatments that facilitate release of proapoptotic intermembrane space proteins
increase mitochondrial biogenesis (Viscomi et al., 2011; Wenz (Frezza et al., 2006). The biogenesis of IM domains is an active
et al., 2008; Yatsuga and Suomalainen, 2012) or that activate process highly dependent on the mitochondrial-specific anionic
AMPK (Viscomi et al., 2011). In these instances, it is likely that lipids, phosphotidylethanolamine and cardiolipin, whose trans-
AMPK activation leads to an increase in NAD+, triggering Sirt1 port and levels within mitochondria are tightly controlled by
activation and subsequent PGC-1a induction of mitochondrial a surprisingly complex set of factors (Osman et al., 2011).
biogenesis (Corton et al., 1995; Golubitzky et al., 2011; Viscomi Through interactions with lipids and through the formation of
et al., 2011). Together, these studies suggest that mitochondrial inner-membrane supercomplexes, abundant inner-membrane
biogenesis is blocked by chronic OXPHOS dysfunction and that proteins, such as adenine nucleotide translocator, are also
increased mitochondrial biogenesis can be beneficial for mito- important for the structural organization of this membrane (Clay-
chondrial disease. pool et al., 2008). In addition, the regulated dimerization/
Recent work has linked tumor suppressors and oncogenes oligomerization of ATP synthase is a major driving force for
directly to metabolic sensing and regulation, and has conse- inner-membrane structure, possibly inducing and/or stabilizing
quently indicated that altered cellular metabolism is a contribu- the curvature of crista membranes (Paumard et al., 2002;
tory and causative factor in cancer. Cancer cells reprogram the Strauss et al., 2008). Dedicated structural assemblies have
use of two key catabolic molecules, glucose and glutamine via also been implicated in the organization of mitochondrial
signaling pathways containing known oncogenes, including membranes (Polianskyte et al., 2009), including recent work
myc and tumor suppressors, such as the LKB1/AMPK (Vander pointing to a large conserved multiprotein Mitofilin complex
Heiden et al., 2009). These signaling pathways shunt glucose (Harner et al., 2011; Hoppins et al., 2011a; von der Malsburg
toward aerobic glycolysis—the so-called Warburg effect (War- et al., 2011). The importance of OM/IM interactions is under-
burg, 1923)—and glutamine toward glutaminolysis for the scored by the observation that the Mitofilin complex, termed
purpose of producing amino acids, nucleotides and lipids that MitOS, also plays a role in the efficiency of mitochondrial protein
are essential for rapid proliferation. In cancer cells, mitochondria import (von der Malsburg et al., 2011), components of which
play a central role via the TCA cycle in the catabolism of gluta- have been implicated in human inherited disorders, including
mine. The altered metabolism of cancer cells raises the possi- neurological (Jin et al., 1996) and cardiac (Davey et al., 2006)
bility that treatments that shift metabolism toward OXPHOS syndromes. Understanding the mechanisms that contribute to
could be therapeutically effective against cancer. Importantly, the structural organization of the inner membrane will decipher
mitochondrial metabolic enzymes have been identified as tumor its functions beyond OXPHOS, such as in mtDNA segregation,
suppressors. Defects in succinate dehydrogenase, fumarate protein import, and mitochondrial dynamics (Brown et al., 2011).
hydratase, and isocitrate dehydrogenase (IDH1) cause inherited The lateral organization of the OM is not as well understood,
paragangliomas, pheochromocytomas, myomas, and gliomas, but it serves as a unique signaling platform for pathways such
respectively (Baysal et al., 2000; Tomlinson et al., 2002; Yan as BCL-2 protein-dependent apoptosis (Chipuk et al., 2010;
et al., 2009). Recent intriguing findings in gliomas indicated Bogner et al., 2010) and innate antiviral immunity, which requires
that IDH1 mutations contribute to gliomas via multiple mecha- the regulated self-assembly of the mitochondrial localized
nisms, including stabilizing hypoxia-inducible factor 1, as was membrane protein, MAVS, into a signaling complex essential
previously found in other tumorigenic TCA defects, and by for anti-inflammatory interferon response (Wang et al., 2011a).
altering the methylation of CpG islands and histones, which Recent superresolution light microscopy techniques have
causes wide-ranging transcriptional consequences that revealed that the OM import TOM complex is localized in clus-
contribute to oncogenesis (Turcan et al., 2012; Lu et al., 2012; ters, whose density and distribution are regulated by growth
Koivunen et al., 2012). The multifaceted roles of IDH1 mutations conditions that alter mitochondrial membrane potential (Wurm
in cancer introduce an intriguing role for mitochondrial function et al., 2011). This observation highlights that events inside mito-
in affecting nuclear genomic expression. chondria regulate the organization and activity of complexes at
the mitochondrial surface, which can influence the external
Connecting Mitochondrial Form and Function structure and behavior of the organelle.
in Homeostasis and Disease The external structure and the cellular location of mitochondria
Mitochondrial form and function are intimately linked. The inner are critical for their function and depend on highly regulated
membrane is highly structured and differentiated into composi- activities such as mitochondrial division and fusion, motility,

Figure 2. Roles of Mitochondrial Dynamics
Red: mitochondria with high membrane potential,
with high oxidative phosphorylation (OXPHOS)
activity. Blue: Mitochondria with low membrane
potential. Mitofusin 1 or 2 (MFN1, MFN2) mediate
mitochondrial outer-membrane fusion in a tissue-
specific manner, and OPA1 (optic atrophy gene 1)
mediates inner-membrane fusion. The zinc met-
alloprotease OMA1 proteolytically cleaves OPA1
under low membrane potential conditions,
promoting fission. Mitochondrial dynamics factors
49 and 51 or mitochondrial fission factor (Mff)
recruit DRP1 onto mitochondria at sites marked by
endoplasmic reticulum tubules (ER), and DRP1
mediates mitochondrial division. In cultured cells,
upon a decrease in mitochondrial membrane
potential, PINK1 kinase recruits Parkin, a ubiquitin
E3 ligase, which ubiquitinates several mito-
chondrial targets, including MFN1 and Miro, to
facilitate the degradation of mitochondria via mi-
tophagy. Parkin-mediated ubiquitination triggers
OMMAD, outer-mitochondrial membrane-associ-
ated degradation—a proteosomal pathway that
degrades ubiquinated OM proteins in a CDC48-
dependent manner. OMMAD is probably cell type-
dependent and may also function in quality
control. In erythrocytes, mitophagy receptor Nix1
is involved in autophagosome recruitment. ER
forms close contacts with mitochondria, essential
for calcium regulation in cellular microcompart-
ments. Miro (blue feet) is a mitochondrial receptor
for kinesin via Milton that facilitates the transport of
mitochondria on microtubules in a Ca2+-regulated
manner. Upon synaptic activity in neurons, influx
of glutamate and Ca2+ halts mitochondrial trans-
port via Miro to position them at sites of synaptic
activity that require Ca2+ uptake and ATP.
and tethering. These activities govern the overall shape, Mitochondrial division and fusion are mediated by the action of
connectedness, and location of mitochondria within cells (Fig- large multidomain dynamin-related GTPases that function via
ure 2). Although little data are currently available, it is clear that self-assembly to remodel diverse membranes in cells (Hoppins
the relative contributions of these activities and the molecular et al., 2007). In mammals, mitochondrial division is mediated
components that mediate them are highly tissue specific—a by a single dynamin-related protein, DRP1, whereas fusion
phenomenon that contributes to the variable manifestations of requires two families of dynamin-like proteins, MFN1/MFN2
human mitochondrial diseases. and OPA1. Evidence suggests that DRP1 divides mitochondria
In metazoans, mitochondrial motility is mediated by Miro, a by forming helical structures that wrap around mitochondria
conserved Ras-like GTPase that links the mitochondrial surface (Ingerman et al., 2005; Labrousse et al., 1999; Yoon et al.,
with the microtubule motor protein kinesin Milton (Glater et al., 2001). Less is known about the mechanism mediating mitochon-
2006; Hollenbeck and Saxton, 2005; Liu and Hajnóczky, 2009; drial fusion, although it is likely that the self-assembly of the
Wang and Schwarz, 2009). Although the exact mechanism is fusion dynamins contributes to membrane tethering and fusion
not understood, Miro serves as a Ca2+ sensor that controls mito- events (DeVay et al., 2009; Griffin and Chan, 2006). The proteins
chondrial motility by virtue of its GTPase domains and its calcium that mediate mitochondrial dynamics are highly regulated and
binding EF hand motifs to couple an increase in cytosolic consequently integrated into cellular signaling pathways. For
calcium to an inhibition of mitochondrial motility (Macaskill example, DRP1 exists as several splice variants and is modified
et al., 2009; Saotome et al., 2008; Wang and Schwarz, 2009). by a plethora of posttranslational modifications, which integrate
This mechanism is particularly important in neurons, where its activity with cellular events, such as apoptosis, Ca2+ sig-
Ca2+ influx occurs at presynaptic terminals and postsynaptic naling, hypoxic response, and the cell cycle (Strack and Cribbs,
dendritic spines due to glutamatergic stimulation. These local 2012).
increases provide a mechanism to halt mitochondria at the site Loss of either fusion or division activity results in dysfunctional
of neuronal activity, and maintain Ca2+ and energetic homeo- mitochondria. One common explanation for the importance of
stasis. In this context, Miro may enable neurons to efficiently mitochondrial fusion is the need for exchange of IMS and
retain mitochondria at the sites with high Ca2+, providing matrix contents, including mtDNA between mitochondria. In
a neuronal protection mechanism. Consistent with this model, this manner, mitochondrial fusion may buffer partially defects
the EF hands of Miro mediate glutamatergic regulation of mito- and transient stresses (Chen et al., 2007, 2010; Nunnari et al.,
chondrial motility and provide a protective mechanism against 1997). In cultured cells, stressors including UV exposure,
excitotoxicity (Wang and Schwarz, 2009). cycloheximide treatment, and nutrient deprivation, stimulate

mitochondrial fusion to generate branched and interconnected chondrial dynamics and in tumors as an antiapoptotic factor
organelles and improve cell survival (Gomes et al., 2011a, link mitochondrial fission and fusion to cancer.
2011b; Rambold et al., 2011; Tondera et al., 2009). Mitochondrial Mitochondrial dynamics are also closely integrated with the
fusion is balanced by mitochondrial division, which creates mitophagy quality control pathway (Twig et al., 2008; Youle and
organelles of the appropriate size for transport along actin or Narendra, 2011). PINK1, an IMS-localized Ser/Thr kinase, and
microtubule networks. Cells that are highly polarized and depen- Parkin, a cytoplasmic E3 ubiquitin ligase, regulate mitophagy
dent on mitochondrial function, such as neurons, are especially in cultured cell models and in fruit-fly muscle. Together these
sensitive to defects in mitochondrial division (Verstreken et al., proteins collaborate to sense and trigger the removal of
2005). A neuronal cell-specific knockout of DRP1 in the mouse ‘‘damaged’’ mitochondria (Clark et al., 2006; Greene et al.,
results in a decrease in neurites and defective synapse forma- 2003; Narendra et al., 2008; Park et al., 2006). Loss of membrane
tion, while an increase in mitochondrial division in cultured potential inhibits the degradation of PINK1 and reroutes it to the
neurons enhances mitochondrial mass and distribution and surface of mitochondria, where it accumulates and recruits Parkin
stimulates synapse formation (Dickey and Strack, 2011; Ishihara (Kim et al., 2008; Lin and Kang, 2008; Matsuda et al., 2010; Nar-
et al., 2009; Li et al., 2004; Wakabayashi et al., 2009). endra et al., 2010; Vives-Bauza et al., 2010; Ziviani et al., 2010).
In cells, inhibition of fusion results in OXPHOS deficiencies, On the mitochondrial surface Parkin ubiquitinates a specific
mtDNA loss, and mitochondrial motility defects, and division subset of OM proteins, resulting in their proteasomal degradation
defects also cause OXPHOS deficiencies and significant by a mechanism that resembles ER-associated degradation
increases in ROS production (Chen et al., 2003, 2007; Hermann pathway (Neutzner et al., 2007; Yoshii et al., 2011; Ziviani et al.,
et al., 1998; Ishihara et al., 2009; Parone et al., 2008; Wakabaya- 2010; Chan et al., 2011; Heo et al., 2010; Tanaka et al., 2010;
shi et al., 2009). In animals, deletions and mutations of the divi- Xu et al., 2011). Another mitophagy pathway functions in erythro-
sion and fusion machinery cause embryonic lethality, and in cyte development, where upon reticulocyte maturation mito-
humans, recessive defects of DRP1 are associated with early chondria are actively eliminated. This mitophagy pathway is
infant mortality and cardiomyopathy (Waterham et al., 2007; dependent on Nix, an OM-associated BH3-only member of
Ashrafian et al., 2010) Mutations in MFN2 and OPA1 cause BCL-2 family proteins, suggesting that Nix functions as a mitoph-
tissue-specific neurodegenerative diseases, Charcot Marie agy receptor (Sandoval et al., 2008; Schweers et al., 2007). This
Tooth 2A (CMT2A) and dominant optic atrophy (DOA), respec- raises the possibility that other tissue- or condition-specific
tively (Alexander et al., 2000; Delettre et al., 2000; Züchner mitophagy receptors exist. The presence of such receptors and
et al., 2004). These pathogenic conditions emphasize the impor- their functions remain to be elucidated. Given the nature of
tant physiological roles and differential requirement of mitochon- mitophagy, such receptors could, in addition to contributing to
drial dynamics in different cell types. quality control, also dramatically impact mtDNA segregation.
Recent studies specifically connect PINK1/Parkin-mediated
Linking Mitochondrial Dynamics with Apoptosis autophagy with mitochondrial dynamics and motility, providing
and Autophagy evidence that Parkin ubiquitinates MFN1, MFN2, and Miro in
Mitochondrial division and fusion also impinge on apoptosis by cultured cells, leading to their degradation and consequently
mechanisms that are not yet fully understood (Martinou and altering mitochondrial behavior (Chan et al., 2011; Gegg et al.,
Youle, 2011). During apoptosis, mitochondria dramatically frag- 2010; Poole et al., 2010; Tanaka et al., 2010; Wang et al.,
ment as a consequence of an increased recruitment of DRP1 to 2011b; Ziviani et al., 2010). In this context, multiple OM-associ-
mitochondria, which is key to the positive regulatory role DRP1 ated ubiquitin ligases have been identified whose substrates
plays in Bax/Bak-mediated mitochondrial outer-membrane per- and roles are largely unknown (Anton et al., 2011; Braschi
meabilization (MOMP) (Frank et al., 2001; Jagasia et al., 2005; et al., 2009; Durr et al., 2006; Nakamura et al., 2006; Neutzner
Wasiak et al., 2007). Although DRP1’s positive role in apoptosis et al., 2008; Tang et al., 2011). Loss of membrane potential
is independent of its role in the regulation of mitochondrial also attenuates mitochondrial fusion via OMA1-mediated
structure per se, mitochondrial shape is likely to be an important cleavage of integral membrane isoforms of OPA1 (Ehses et al.,
factor in MOMP (Cassidy-Stone et al., 2008; Montessuit et al., 2009; Head et al., 2009). Consistently, mitophagy is attenuated
2010). In contrast, mitochondrial fusion protects cells from in cells with decreased mitochondrial division and/or increased
apoptotic cell death, and activation of apoptosis coordinately fusion activities likely because larger organelles are occluded
inhibits fusion activity (Lee et al., 2004; Olichon et al., 2003; from autophagosomes. Indeed, nutrient starvation in cultured
Sugioka et al., 2004). This protection is in part due to the role of cells induces the formation of a hyperfused mitochondrial
OPA1 in the integrity of crista junctions and its ability to limit the network, which protects mitochondria from elimination via
release of proapoptotic IMS components (Cipolat et al., 2006; mitophagy (Gomes et al., 2011a; Rambold et al., 2011). In flies,
Frezza et al., 2006). Conversely, BCL-2 proteins play regulatory attenuation of mitochondrial fusion or stimulation of mitochon-
roles in mitochondrial dynamics in healthy cells, where they stim- drial division can rescue phenotypes associated with PINK1 or
ulate fusion (Cleland et al., 2011; Hoppins et al., 2011b; Karbow- Parkin mutants, and loss of division exacerbates these pheno-
ski et al., 2006; Rolland et al., 2009). The regulatory network types and causes lethality (Deng et al., 2008; Poole et al.,
formed by BCL-2 proteins and mitochondrial dynamics proteins 2008). Thus, evidence is consistent with the idea that mitophagy
may be a contributory factor in the human neurodegenerative is a pathway that coordinately regulates mitochondrial structure
diseases associated with mutations in MFN2 and OPA1 (Olichon and motility to effectively segregate damaged mitochondria from
et al., 2007). Furthermore, the roles of BCL-2 in regulating mito- a healthy network in cells, which facilitates their degradation.

(Davis et al., 1979; Langston et al., 1983; Vyas et al., 1986).
Gene defects that lead to mtDNA mutations, such as dominant
mutations of mitochondrial DNA polymerase gamma, also cause
PD (Luoma et al., 2004). These observations highlight the
complex multifactorial nature of neurodegeneration and point
to the need for additional animal studies to elucidate physiolog-
ical roles of mitophagy and its contribution to PD.
Altered mitochondrial dynamics have also been implicated in
neurodegeneration. In cell culture models for neurodegenerative
diseases, such as Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease, and amyotrophic lateral sclerosis, mito-
chondria typically fragment in response to the expression of mis-
folded proteins (Cho et al., 2010; Costa et al., 2010; Lutz et al.,
2009; Shirendeb et al., 2012; Song et al., 2011; Wang et al.,
2009). Although it is not clear whether mitochondrial fragmenta-
tion is a cause or a consequence of the pathogenic process,
inhibition of mitochondrial division attenuates disease-associ-
ated phenotypes in multiple models of neurodegenerative
disease (Cassidy-Stone et al., 2008; Cui et al., 2010; Lackner
and Nunnari, 2010). Inhibiting division may also attenuate the
ubiquitin dependent turnover of outer-membrane proteins and
Figure 3. Interorganellar Communication mitophagy, which would allow essential behaviors like mito-
Ub, ubiquitin; red and blue, proteins in mitochondrial outer membrane are
PINK1, a mitochondrial kinase, and the E3 ubiquitin ligase Parkin, recruited
chondrial motility to be retained. In this context, it is possible
onto mitochondria by PINK1; MDV, mitochondria-derived vesicle; NAD, that the mitochondrial motility defects associated with absent
nicotinamide adenine dinucleotide, oxidized form; NADH, nicotinamide or altered MFN1 and MFN2 proteins result from the targeted
adenine dinucleotide, reduced form; AMP, adenosine monophosphate; ATP,
degradation of Miro (Baloh et al., 2007; Chen et al., 2005).
adenosine triphosphate; ER, endoplasmic reticulum, tubules of which are
marking sites of mitochondrial division; MAVS, mitochondrial antiviral The role of mitochondrial division and its potential as a thera-
signaling, which is activated by viral RNA; MAM, mitochondrial-associated peutic target for neurodegeneration needs to be further explored
endoplasmic reticulum membrane. in relevant animal models. In addition, as mitochondrial division
is essential in mammals, this pathway may have limited thera-
The relevance of the PINK1/Parkin mitochondrial turnover peutic potential for neurodegeneration. However, more acute
pathway in animal models has not yet been established; ischemic reperfusion injuries and drug toxicities are also associ-
however, defects in this pathway have been suggested to ated with increased mitochondrial fragmentation in cultured cells
play a role in the development of Parkinson’s disease (PD), models and in animal models of myocardial infarction and drug
where a role of PINK1 and Parkin were originally characterized induced renal toxicity, inhibition of mitochondrial division has
as their mutant forms cause familial early-onset PD (Kitada shown therapeutic promise (Brooks et al., 2009; Ong et al.,
et al., 1998; Valente et al., 2004). The association of PINK1/ 2010).
Parkin to PD points to their essential role in maintenance of
dopaminergic neurons, the cell type in substantia nigra of The Roles of Interorganellar Contacts
mesencephalon that most severely degenerates in PD. Data in Mitochondrial Biology
from cell culture models suggest the intriguing possibility that Mitochondrial distribution and dynamics are influenced by
defective mitochondrial quality control contributes more gener- intimate physical connections between the mitochondrial
ally to Parkinson-like phenotypes, potentially explaining why outer membrane and diverse intracellular membranes, such as
mtDNA mutation accumulate in substantia nigra neurons the plasma membrane, peroxisomes, ER, autophagosome,s
(Bender et al., 2006; Kraytsberg et al., 2006). A recent mouse and lysosomes, termed mitochondria-associated membranes
study, however, questions this simple model. In the PD Mitopark (MAMs) (Figure 3). MAMs create unique environments or
mouse model, progressive depletion of mtDNA in dopaminergic platforms for the localization and activity of components that
neurons does not lead to the accumulation of mitochondrial function in shared interorganellar functions, such as Ca2+
Parkin, and loss of Parkin does not affect neurological disease homeostasis and lipid biosynthesis (Hayashi et al., 2009; Rizzuto
progression (Sterky et al., 2011). This raises the possibility that and Pozzan, 2006; Voelker, 2009). Physical tethers are also
PINK1/Parkin contribute to PD by mechanisms other than mi- thought to be important to stably position mitochondria at
tophagy. Parkin has been implicated in nonneuronal mediated specific locations within cells, for example, in the axons and
lipid uptake regulation, raising the possibility that altered lipid dendrites of neurons or in muscle fibers for efficient energy utili-
metabolism contributes to Parkin-linked PD (Kim et al., 2011). zation (Garcı́a-Pérez et al., 2011; Kang et al., 2008).
Additionally, mitochondrial dysfunction is linked to PD by early Communication of mitochondria with intracellular structures
toxicological studies on MPTP, a compound that is metabolized also occurs via small vesicles that bud off of mitochondria in
into a complex I inhibitor, MPP+. MPP+ selectively accumulates a DRP1-independent manner (Neuspiel et al., 2008). Interest-
in dopaminergic cells and causes symptoms of PD in humans ingly, treatment of cells with antimycin A, an inhibitor of complex

Figure 4. Organismal Effects of Mitochondrial Respiratory Chain Deficiency
Skeletal muscle interprets mitochondrial OXPHOS defect as a starvation response in the presence of normal nutrition. The defective muscle fibers secrete FGF21,
a hormone-like cytokine, to blood circulation, mobilizing lipids from storage fat, affecting whole-organismal lipid metabolism as a chronic response.
III, stimulates the biogenesis of vesicles that carry mitochondrial chronic lipid recruitment from adipose tissue and metabolic
cargo that fuse with lysosomes, suggesting that this pathway derangement (Figure 4). Another muscle-secreted cytokine, iri-
functions in quality control (Soubannier et al., 2012). sin, was recently shown to mediate the differentiation of white
A role for ER mitochondrial contacts has been shown in both adipose cells to brown fat in response to exercise and PGC-
mitochondrial division and in apoptosis, which has broader 1alpha-induced mitochondrial biogenesis in skeletal muscle
implications for understanding how mitochondrial dysfunction (Boström et al., 2012). A non-cell-autonomous mitochondrial
contributes to disease. Ca2+ release at ER-mitochondrial regulatory pathway was also reported in C. elegans: a tissue-
contacts may sensitize mitochondria to apoptotic effectors specific RNA interference-mediated knockdown of cytochrome
(Breckenridge et al., 2003; Iwasawa et al., 2011; Tabas and c oxidase subunit in neurons causes a local cellular stress
Ron, 2011). During mitochondrial division, ER tubules wrap response in neurons that is also communicated to the gut (Dur-
around and likely constrict mitochondria and mark sites of ieux et al., 2011). The cellular response is an unfolded protein
mitochondrial division—a process conserved from yeast to stress response pathway specific to mitochondria (UPRmt)
mammals (Friedman et al., 2011). In this context, the observation that also exists in mammals (Haynes and Ron, 2010). UPRmt
that Bax colocalizes with DRP1 at sites of mitochondrial originates in mitochondria from the accumulation of unassem-
constriction during apoptosis (Karbowski et al., 2002; Nechush- bled respiratory complex subunits and is communicated to the
tan et al., 2001) raises the possibility that Bax-dependent MOMP nucleus via an unknown mechanism where it culminates in the
occurs at and depends on regions of ER-mitochondria contact. regulated expression of mitochondrial protein chaperones,
ER stress and mitochondrial dysfunction have been implicated such as HSP-60 (Benedetti et al., 2006; Haynes et al., 2007; Hay-
in a shared set of diseases associated with altered mitochondrial nes and Ron, 2010; Yoneda et al., 2004; Zhao et al., 2002). The
dynamics. Thus, these observations raise the possibility that mechanism by which activation of the UPRmt is propagated in
alterations in ER-mitochondrial contacts are a contributory a non-cell-autonomous manner is also not known, but has
factor in human disease (Schon and Przedborski, 2011). been speculated to occur via a ‘‘mitokine’’ that signals OXPHOS
deficiency to the whole organism. In addition to peptides, candi-
Organismal Roles of Mitochondria dates for long range signaling molecules include metabolites and
Recent studies demonstrate that a defect in mitochondrial func- amino acids, whose levels can be easily sensed by over consid-
tion in one tissue has consequences for the whole organism and erable distances by cells and tissues. The finding that a single
have expanded our view of mitochondria beyond their cell auton- dysfunctional tissue or cell can tune or reprogram the whole
omous roles. In mouse models of mitochondrial disease and in organism via secreted signaling molecules is a new concept in
human patients, OXPHOS-deficient skeletal muscle secretes mitochondrial disease. These relatively unexplored pathways
FGF21, a cytokine that enters the blood and circulates (Suoma- are likely an essential part of pathogenesis and by their secretory
lainen et al., 2011; Tyynismaa et al., 2010) (Figure 4). FGF21 is nature are attractive targets for therapy.
a fasting-related hormone, which induces ketogenesis in the liver Several outstanding questions are raised by these observa-
and mobilizes lipids from adipose tissue for oxidation (Badman tions. Are only some tissues capable of initiating whole-organism
et al., 2009; Hotta et al., 2009; Kharitonenkov et al., 2005). In energy metabolic reprogramming? In humans, brain-specific
mitochondrial disease, FGF21 is constitutively secreted from mitochondrial disorders show low FGF21 levels (Suomalainen
pseudostarving OXPHOS-deficient muscle fibers, resulting in et al., 2011), suggesting that brain tissue is not the source for

FGF21 secretion. Does chronic starvation produce harmful the Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Academy
signals that influence disease progression? Is signaling limited of Finland, European Research Council, University of Helsinki, and Helsinki
University Central Hospital. The authors wish to thank Helena Schmidt for
to energy deficiency, or can other organelles induce cytokine re-
figure art.
programming as well? Answers to these questions will provide
crucial insight into the tissue specific manifestations of mito-
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Introduction ancestry of mitochondria and bacteriophage-related mtDNA

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