Papers by Frank Gellerich
Small molecules such as adenine nucleotides can pass the porin pores of mitochondrial outer membr... more Small molecules such as adenine nucleotides can pass the porin pores of mitochondrial outer membrane (VDAC) for exchange between mitochondria and cytosol. Estimated to range from 1.25 to 2 × 10-9 m (Colombini et al., 1987), the radius of the pores is sufficient to allow the passage of molecules up to a molecular weight of 6000 (Zalman et al., 1980). The effective cross-section of pores is influenced by voltage-dependent processes (Colombini et al., 1987) or colloid-osmotic effects (Zimmerberg & Parsegian, 1986). Nevertheless, the intermembrane space together with the extramitochondrial compartment is commonly believed to form a homogeneous pool for adenine nucleotides. However, it may be assumed that the transport of adenine nucleotides between the cytosol and the AdN translocator occurs by diffusion along concentration gradients, but the question arises whether or not these gradients are high enough to cause a measurable AdN compartmentation in the intermembrane space. Since concentration gradients are necessarily connected with fluxes and disappear with them, the term dynamic compartmentation has been proposed for diffusion-dependent inhomogeneities (Gellerich et al., 1987).
Experimental Neurology, May 1, 2021
Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative diso... more Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ10 (5 μM for 3 weeks) or Trolox (300 μM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors.
Archives of Biochemistry and Biophysics, Aug 1, 2015
ABSTRACT The mitochondrial peptidyl prolyl isomerase cyclophilin D (CypD) activates permeability ... more ABSTRACT The mitochondrial peptidyl prolyl isomerase cyclophilin D (CypD) activates permeability transition (PT). To study the role of CypD in this process we compared the functions of brain mitochondria isolated from wild type (BMWT) and CypD knockout (Ppif(-/-)) mice (BMKO) with and without CypD inhibitor Cyclosporin A (CsA) under normal and Ca(2+) stress conditions. Our data demonstrate that BMKO are characterized by higher rates of glutamate/malate-dependent oxidative phosphorylation, higher membrane potential and higher resistance to detrimental Ca(2+) effects than BMWT. Under the elevated Ca(2+) and correspondingly decreased membrane potential the dose response in BMKO shifts to higher Ca(2+) concentrations as compared to BMWT. However, significantly high Ca(2+) levels result in complete loss of membrane potential in BMKO, too. CsA diminishes the loss of membrane potential in BMWT but has no protecting effect in BMKO. The results are in line with the assumption that PT is regulated by CypD under the control of matrix Ca(2+). Due to missing of CypD the BMKO can favor PT only at high Ca(2+) concentrations. It is concluded that CypD sensitizes the brain mitochondria to PT, and its inhibition by CsA or CypD absence improves the complex I-related mitochondrial function and increases mitochondria stability against Ca(2+) stress. Copyright © 2015. Published by Elsevier Inc.
Biochimica Et Biophysica Acta - Bioenergetics, Aug 1, 1993
ABSTRACT
Biochemical and Biophysical Research Communications, Feb 1, 2023
Biochemical and Biophysical Research Communications, Feb 1, 2023
Thoracic and Cardiovascular Surgeon, 2023
Thoracic and Cardiovascular Surgeon, 2021
Journal of Biological Chemistry, 2020
Journal of Cellular and Molecular Medicine, 2020
Cardiac ischaemia‐reperfusion (I/R) injury has been attributed to stress signals arising from an ... more Cardiac ischaemia‐reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS production. Hence, AOX represents a natural rescue mechanism from respiratory stress. This study aimed to determine how respiratory restoration through xenotopically expressed AOX affects the re‐perfused post‐ischaemic mouse heart. As expected, AOX supports ETC function and attenuates the ROS load in post‐anoxic heart mitochondria. However, post‐ischaemic cardiac remodelling over 3 and 9 weeks was not improved. AOX blunted transcript levels of factors known to be up‐regulated upon I/R such as the at...
Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2018
Modern Trends in Biothermokinetics, 1993
The regulation of oxidative phosphorylation in muscle is still a matter of dispute. To clarify th... more The regulation of oxidative phosphorylation in muscle is still a matter of dispute. To clarify the discrepancies in the literature, a detailed reinvestigation of the distribution of flux control in the process of oxidative phosphorylation in muscle mitochondria seems to be of importance. Moreover, large variations in the phosphate concentration are known to occur in muscle1. Possible effects of those changes have to be taken into consideration due to observations made with rat liver mitochondria that the distribution of flux control seems to depend on phosphate concentration2,3.
Molecular Biology of Mitochondrial Transport Systems, 1994
In the past, the biological relevance of mitochondrially localized ATP splitting enzymes such as ... more In the past, the biological relevance of mitochondrially localized ATP splitting enzymes such as hexokinase or creatine kinase has been discussed as an advantage in supplying these enzymes with mitochondrially formed ATP (Saks et al., 1974; Gellerich et al., 1977; Bessman & Gots, 1975). A new approach to this problem became possible through experiments with reconstituted systems (Gosalvez et al., 1974; Gellerich & Saks, 1982; Gellerich et al., 1987; Kottke et al., 1991), in which mitochondria and muscle pyruvate kinase compete for ADP produced by kinases in varied localization with respect to the mitochondrial outer membrane. For mitochondria from heart (Gellerich & Saks, 1982), liver (Gellerich, 1992), and brain (Kottke et al., 1991) it was shown that the ADP supply to oxidative phosphorylation was privileged via mitochondrial creatine kinase or adenylate kinase compared to the ADP supply by extramitochondrially added enzymes such as yeast hexokinase. Therefore, channelling of the extramitochondrially formed ADP into the mitochondria seems to be the crucial problem in cellular bioenergetics (Gellerich & Saks, 1982). In the resting muscle the cytosolic ADP is in the micromolar range whereas the concentrations of ATP, creatine phosphate and creatine are in the millimolar range (Wallimann et al., 1992). The low cytosolic ADP concentration is advantageous to the thermodynamic efficiency of the cell work but does not allow an optimal stimulation of oxidative phosphorylation. It is assumed that it is one of the main functions of the creatine phosphate shuttle to transport ADP into the mitochondria at low extramitochondrial ADP concentrations. In spite of extensive studies, the mechanism of the creatine phosphate shuttle is not yet completely understood. It was suggested that the compartmentalized creatine kinase isoenzymes may transport ADP by means of a metabolite shuttle (For a recent review see Wallimann et al., 1992). The general mechanism of metabolite shuttle is shown in the upper part of Fig. 1. In contrast to other well established metabolite shuttles such as the malate/aspartate shuttle which transport metabolites (hydrogen) through the mitochondrial inner membrane into the matrix space, metabolite shuttles into the mitochondrial intermembrane space are considered here. Therefore, these shuttles do not require translocator proteins, since their metabolites can diffuse through the porin pores. The metabolite A is reversibly transformed into the metabolite B. Both or only B diffuse into the intermembrane space, thus increasing the transport rate of A into the compartment. It is a prerequisite for a metabolite shuttle that the reaction A B has different directions in both compartments. In the lower part of Fig. 1, two shuttles are shown which are probably special forms of the general mechanism. One is the widely accepted creatine phosphate shuttle (Wallimann et al., 1992). As in the general scheme, the mitochondrial and the extramitochondrial creatine kinases act in different directions. Furthermore, this shuttle needs a sufficiently high creatine concentration since creatine instead of ADP (or both at elevated ADP concentrations) has to diffuse into the mitochondrial intermembrane space forming there ADP via mitochondrial creatine kinase. As a second ADP shuttle we propose the adenylate kinase shuttle acting in a way similar to that of the creatine phosphate shuttle. It may operate in tissues with sufficiently high adenylate kinase activities such as liver, some types of spermatozoa or muscles. This could be possible, since mitochondrial and cytosolic adenylate kinase isoenzymes are compartmentalized in a way similar to that of the creatine kinase isoenzymes. In this shuttle, AMP carries ADP equivalents (just as creatine) into the mitochondria: AMP formed in the cytosol from ADP via cytosolic adenylate kinase diffuses into the intermembrane space forming there ADP via mitochondrial adenylate kinase, and this ADP stimulates the oxidative phosphorylation.
Preface. Part 1: Noninvasive Detection of Mitochondrial Function. Part 2: Bioenergetic Investigat... more Preface. Part 1: Noninvasive Detection of Mitochondrial Function. Part 2: Bioenergetic Investigation of Isolated Mitochondria, Skinned Muscle Fibers and Cells. Part 3: Mitochondrial Transition Pore, Radicals and Diseases. Part 4: Mitochondrial Genome and Diseases. Part 5: Ageing, Mitochondria and Diseases.
Modern Trends in Biothermokinetics, 1993
Both the kinetics and thermodynamics of the creatine kinase reaction has been studied in great de... more Both the kinetics and thermodynamics of the creatine kinase reaction has been studied in great detail1–3. In these studies the soluble or solubilized isoenzymes of creatine kinase have been used. However, in the cells in vivo the creatine kinase isoenzymes function mostly in the coupled state both in mitochondria and myofibrils as well as at the cellular membranes forming the intracellular phosphocreatine pathway, or “phosphocreatine circuit” for the energy channeling4–9. In this work we investigated the thermodynamic and kinetic aspects of coupling of the creatine kinase to the oxidative phosphorylation in mitochondria.
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Papers by Frank Gellerich