Inhibition of Mitochondrial Na (cid:1) -Ca 2 (cid:1) Exchange Restores Agonist-induced ATP Production and Ca 2 (cid:1) Handling in Human Complex I Deficiency*

Human mitochondrial complex I (NADH:ubiquinone oxidoreductase) of the oxidative phosphorylation system is a multiprotein assembly comprising both nuclear and mitochondrially encoded subunits. Deficiency of this complex is associated with numerous clinical syndromes ranging from highly progressive, often early lethal encephalopathies, of which Leigh disease is the most frequent, to neurodegenerative disorders in adult life, including Leber's hereditary optic neuropathy and Parkinson disease. We show here that the cytosolic Ca2+ signal in response to hormonal stimulation with bradykinin was impaired in skin fibroblasts from children between the ages of 0 and 5 years with an isolated complex I deficiency caused by mutations in nuclear encoded structural subunits of the complex. Inhibition of mitochondrial Na+-Ca2+ exchange by the benzothiazepine CGP37157 completely restored the aberrant cytosolic Ca2+ signal. This effect of the inhibitor was paralleled by complete restoration of the bradykinin-induced increases in mitochondrial Ca2+ concentration and ensuing ATP production. Thus, impaired mitochondrial Ca2+ accumulation during agonist stimulation is a major consequence of human complex I deficiency, a finding that may provide the basis for the development of new therapeutic approaches to this disorder.

[1]  S. Dimauro,et al.  Comparative biochemical studies in fibroblasts from patients with different forms of Leigh syndrome , 1996, Journal of Inherited Metabolic Disease.

[2]  David E. Clapham,et al.  The mitochondrial calcium uniporter is a highly selective ion channel , 2004, Nature.

[3]  B. V. van Engelen,et al.  Upregulation of Ca2+ removal in human skeletal muscle: a possible role for Ca2+-dependent priming of mitochondrial ATP synthesis. , 2003, American journal of physiology. Cell physiology.

[4]  Sten Orrenius,et al.  Calcium: Regulation of cell death: the calcium–apoptosis link , 2003, Nature Reviews Molecular Cell Biology.

[5]  M. Madesh,et al.  Calcium signaling and apoptosis. , 2003, Biochemical and biophysical research communications.

[6]  R. Rizzuto,et al.  Mitochondrial Ca2+ Uptake Requires Sustained Ca2+ Release from the Endoplasmic Reticulum* , 2003, The Journal of Biological Chemistry.

[7]  W. Koopman,et al.  R-Ras Alters Ca2+ Homeostasis by Increasing the Ca2+ Leak across the Endoplasmic Reticular Membrane* , 2003, The Journal of Biological Chemistry.

[8]  R. Pfundt,et al.  Human mitochondrial complex I deficiency: investigating transcriptional responses by microarray. , 2003, Neuropediatrics.

[9]  G. Baird,et al.  Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria , 2002, The Journal of cell biology.

[10]  M. Montero,et al.  Measuring [Ca2+] in the endoplasmic reticulum with aequorin. , 2002, Cell calcium.

[11]  G. Rutter,et al.  Glucose-stimulated oscillations in free cytosolic ATP concentration imaged in single islet beta-cells: evidence for a Ca2+-dependent mechanism. , 2002, Diabetes.

[12]  M. Madesh,et al.  VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release , 2001, The Journal of cell biology.

[13]  S. Dimauro,et al.  The genetics and pathology of oxidative phosphorylation , 2001, Nature Reviews Genetics.

[14]  R. Carrozzo,et al.  The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome , 2001, Neurology.

[15]  H. Mandel,et al.  Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy , 2001, Annals of neurology.

[16]  G. Rutter,et al.  Mitochondrial priming modifies Ca2+ oscillations and insulin secretion in pancreatic islets. , 2001, The Biochemical journal.

[17]  L. V. D. Heuvel,et al.  Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene. , 2000, Biochemical and biophysical research communications.

[18]  U. Brandt,et al.  Application of the obligate aerobic yeast Yarrowia lipolytica as a eucaryotic model to analyse Leigh syndrome mutations in the complex I core subunits PSST and TYKY. , 2000, Biochimica et biophysica acta.

[19]  U. Brandt,et al.  Function of Conserved Acidic Residues in the PSST Homologue of Complex I (NADH:Ubiquinone Oxidoreductase) from Yarrowia lipolytica * , 2000, The Journal of Biological Chemistry.

[20]  G. Rutter,et al.  Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  E. Schon,et al.  A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency , 1999, Nature Medicine.

[22]  P. Barth,et al.  Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I , 1999, Annals of neurology.

[23]  J C Reed,et al.  Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. , 1999, Science.

[24]  S. Patel,et al.  Molecular properties of inositol 1,4,5-trisphosphate receptors. , 1999, Cell calcium.

[25]  E. Mariman,et al.  Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy , 1999, Nature Genetics.

[26]  P. Bernardi,et al.  Mitochondrial transport of cations: channels, exchangers, and permeability transition. , 1999, Physiological reviews.

[27]  G. Hajnóczky,et al.  Quasi‐synaptic calcium signal transmission between endoplasmic reticulum and mitochondria , 1999, The EMBO journal.

[28]  B. Hamel,et al.  The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. , 1998, American journal of human genetics.

[29]  G. Rutter,et al.  Integrating cytosolic calcium signals into mitochondrial metabolic responses , 1998, The EMBO journal.

[30]  E. Mariman,et al.  Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. , 1998, American journal of human genetics.

[31]  S. Orrenius,et al.  The role of calcium in apoptosis. , 1998, Cell calcium.

[32]  E. Pennisi Linker Histones, DNA's Protein Custodians, Gain New Respect , 1996, Science.

[33]  S. Snyder,et al.  Lymphocyte Apoptosis: Mediation by Increased Type 3 Inositol 1,4,5-Trisphosphate Receptor , 1996, Science.

[34]  B. Robinson,et al.  Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. , 1996, The Journal of clinical investigation.

[35]  C. Milstein,et al.  Nonsense Mutations Inhibit RNA Splicing in a Cell-Free System: Recognition of Mutant Codon Is Independent of Protein Synthesis , 1996, Cell.

[36]  M. Brini,et al.  Monitoring dynamic changes in free Ca2+ concentration in the endoplasmic reticulum of intact cells. , 1995, The EMBO journal.

[37]  György Hajnóczky,et al.  Decoding of cytosolic calcium oscillations in the mitochondria , 1995, Cell.

[38]  R Marsault,et al.  Transfected Aequorin in the Measurement of Cytosolic Ca2+ Concentration ([Ca2+]c) , 1995, The Journal of Biological Chemistry.

[39]  M. Goldberg,et al.  Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[40]  K. Gunter,et al.  Transport of calcium by mitochondria , 1994, Journal of bioenergetics and biomembranes.

[41]  T. Pozzan,et al.  Mitochondrial Ca2+ homeostasis in intact cells , 1994, The Journal of cell biology.

[42]  J. De Pont,et al.  Heterogeneity between intracellular Ca2+ stores as the underlying principle of quantal Ca2+ release by inositol 1,4,5-trisphosphate in permeabilized pancreatic acinar cells. , 1994, The Journal of biological chemistry.

[43]  T. Pozzan,et al.  Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. , 1993, Science.

[44]  T. Pozzan,et al.  Stimulated Ca2+ influx raises mitochondrial free Ca2+ to supramicromolar levels in a pancreatic beta-cell line. Possible role in glucose and agonist-induced insulin secretion. , 1993, The Journal of biological chemistry.

[45]  T. Friedrich,et al.  The gene locus of the proton-translocating NADH: ubiquinone oxidoreductase in Escherichia coli. Organization of the 14 genes and relationship between the derived proteins and subunits of mitochondrial complex I. , 1993, Journal of molecular biology.

[46]  M. A. Matlib,et al.  A role for the mitochondrial Na(+)-Ca2+ exchanger in the regulation of oxidative phosphorylation in isolated heart mitochondria. , 1993, The Journal of biological chemistry.

[47]  Tullio Pozzan,et al.  Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin , 1992, Nature.

[48]  James Watras,et al.  Bell-shaped calcium-response curves of lns(l,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum , 1991, Nature.

[49]  G. Steele,et al.  Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[50]  D. Glerum,et al.  The Use of Skin Fibroblast Cultures in the Detection of Respiratory Chain Defects in Patients with Lacticacidemia , 1990, Pediatric Research.

[51]  R. Denton,et al.  Ca2+ as a second messenger within mitochondria of the heart and other tissues. , 1990, Annual review of physiology.

[52]  G. Rutter Ca2(+)-binding to citrate cycle dehydrogenases. , 1990, The International journal of biochemistry.

[53]  F. Assimacopoulos-Jeannet,et al.  Vasopressin and/or glucagon rapidly increases mitochondrial calcium and oxidative enzyme activities in the perfused rat liver. , 1986, The Journal of biological chemistry.