Impaired mitochondrial Ca2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels

Kleist-Retzow, Jürgen-Christoph von; Hornig-Do, Hue-Tran; Schauen, Matthias; Eckertz, Sabrina; Dinh, Tuan; Stassen, Frank R. M.; Lottmann, Nadine; Bust, Maria; Galunska, B.; Wielckens, Klaus; Hein, W.; Beuth, J.; Braun, Jan-Matthias; Fischer, J. H.; Ganitkevich, Vladimir; Maniura‐Weber, Katharina; Wiesner, Rudolf J.

doi:10.1016/j.yexcr.2007.04.015

Cited by 56 publications

(33 citation statements)

References 33 publications

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“…In agreement with this idea, cells with impaired OXPHOS function were found to generate ATP via the glycolytic pathway when grown in a medium containing both D-glucose and pyruvate (16). Similarly, it was demonstrated that glycolysis was increased in 143B cybrid cells with pathogenic mtDNA point mutations (60). Finally, mouse hearts depleted of mtDNA by ablation of the tfam gene displayed a global switch from oxidative to glycolytic metabolism (20).…”

Section: Discussionmentioning

confidence: 70%

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Koopman

Distelmaier²,

Hink³

et al. 2008

American Journal of Physiology-Cell Physiology

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Willems PH. Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria. Am J Physiol Cell Physiol 294: C1124-C1132, 2008. First published March 19, 2008 doi:10.1152/ajpcell.00079.2008.-Mitochondria continuously change shape, position, and matrix configuration for optimal metabolite exchange. It is well established that changes in mitochondrial metabolism influence mitochondrial shape and matrix configuration. We demonstrated previously that inhibition of mitochondrial complex I (CI or NADH:ubiquinone oxidoreductase) by rotenone accelerated matrix protein diffusion and decreased the fraction and velocity of moving mitochondria. In the present study, we investigated the relationship between inherited CI deficiency, mitochondrial shape, mobility, and matrix protein diffusion. To this end, we analyzed fibroblasts of two children that represented opposite extremes in a cohort of 16 patients, with respect to their residual CI activity and mitochondrial shape. Fluorescence correlation spectroscopy (FCS) revealed no relationship between residual CI activity, mitochondrial shape, the fraction of moving mitochondria, their velocity, and the rate of matrix-targeted enhanced yellow fluorescent protein (mitoEYFP) diffusion. However, mitochondrial velocity and matrix protein diffusion in moving mitochondria were two to three times higher in patient cells than in control cells. Nocodazole inhibited mitochondrial movement without altering matrix EYFP diffusion, suggesting that both activities are mutually independent. Unexpectedly, electron microscopy analysis revealed no differences in mitochondrial ultrastructure between control and patient cells. It is discussed that the matrix of a moving mitochondrion in the CI-deficient state becomes less dense, allowing faster metabolite diffusion, and that fibroblasts of CI-deficient patients become more glycolytic, allowing a higher mitochondrial velocity.

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Section: Discussionmentioning

confidence: 70%

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Koopman

Distelmaier²,

Hink³

et al. 2008

American Journal of Physiology-Cell Physiology

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“…Although this issue was not addressed directly, a large number of additional studies of mtDNA diseases, which are not limited to isolated defects of complex I, have revealed features that are consistent with PTP deregulation. These include alterations of Ca 2ϩ homeostasis (47,48,52,53,57), increased reactive oxygen species production (50,51), early alterations of respiration and/or membrane potential (69 -72), and sensitization to Fas-induced apoptosis (73). Assessing whether the altered threshold for PTP opening identified here is a general feature of mtDNA diseases may not only add to our understanding of their pathogenesis but also provide a strategy for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 94%

“…Once this occurs, repolarization cannot take place despite ATP hydrolysis. Based on the protective effect of the intracellular Ca 2ϩ chelator BAPTA-AM and of the antioxidant Trolox, we think that defective complex I sensitizes the PTP through Ca 2ϩ overload and increased production of reactive oxygen species (46), which have indeed been described in several mtDNA disease models (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57).…”

Section: Discussionmentioning

confidence: 97%

Respiratory Complex I Dysfunction Due to Mitochondrial DNA Mutations Shifts the Voltage Threshold for Opening of the Permeability Transition Pore toward Resting Levels

Porcelli

Angelin

Ghelli

et al. 2009

Journal of Biological Chemistry

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We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an ϳ50% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca 2؉ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca 2؉ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases.NADH:ubiquinone oxidoreductase (respiratory complex I; EC 1.6.5.3) is the first multiprotein complex of the oxidative phosphorylation system. Complex I contributes to the formation of the proton electrochemical gradient across the inner mitochondrial membrane by coupling proton translocation to electron transfer from NADH to ubiquinone. The proton gradient provides the driving force for ATP synthesis, ion transport, and maintenance of antioxidant defenses (1). Complex I is the largest respiratory chain complex with an estimated molecular mass of 900,000 Da; it is made up of seven subunits encoded by mtDNA (ND1-6 and ND4L) and 35 or more subunits encoded by nuclear genes (2, 3). Mutations in both the mitochondrial-encoded and the nuclearencoded human genes are known to cause complex I dysfunction, which is associated to a wide array of neurodegenerative diseases (3, 4) and to some types of tumor (5, 6). Pathogenic mutations have been identified in each of the seven NADH dehydrogenase (ND) 3 genes encoded by mtDNA. The clinical symptoms range from single organ or tissue diseases like Leber hereditary optic neuropathy (LHON) (7) to multisystemic disorders like mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and Leigh syndrome (3, 4).It is established that mitochondrial dysfunction is strictly associated to activation of the intrinsic apoptotic pathway activated by the release of cytochrome c from mitochondria (8). In particular, complex I deficiency may sensitize cells to the action of death agonists that permeabilize the outer membrane, such as Bax, through mitocho...

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“…In 2007, another study performed on cybrid cells incorporating two pathogenic mitochondrial mutations (nt 3243 A/G, nt 3202 A/G) reveal that the decreased ATP production by oxidative phosphorylation was compensated by a rise in anaerobic glycolysis. Regarding Ca 2+ homeostasis, these cells did not show any alteration of Ca 2+ signals in the cytosol but take longer to clear up the histamine induced Ca 2+ signal in the mitochondria (von Kleist-Retzow et al, 2007). All over, these studies revealed a deranged Ca 2+ homeostasis in OXPHOS diseases linked to mitochondrial mutations.…”

Section: Calcium Deregulation In Melas Merrf Narp and Lhonmentioning

confidence: 80%

Mitochondrial Calcium Signalling: Role in Oxidative Phosphorylation Diseases

Oulès¹,

Dolores²,

Chami³

2012

Bioenergetics

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Impaired mitochondrial Ca2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels

Cited by 56 publications

References 33 publications

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Respiratory Complex I Dysfunction Due to Mitochondrial DNA Mutations Shifts the Voltage Threshold for Opening of the Permeability Transition Pore toward Resting Levels

Mitochondrial Calcium Signalling: Role in Oxidative Phosphorylation Diseases

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