Mitochondrial Respiratory Complex I: Structure, Function and Implication in Human Diseases

Sharma, Lokendra; Lü, Jianxin; Bai, Yidong

doi:10.2174/092986709787846578

Cited by 279 publications

(225 citation statements)

References 146 publications

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“…To test if SB3 shields cells from oxidative stress by inhibiting ROS-dependent pore opening we performed a whole-cell Ca 2+ -retention capacity (CRC) assay [34], which measures the Ca 2+ threshold for PTP opening in permeabilized cells exposed to a train of repeated Ca 2+ pulses, as accumulation of Ca 2+ into mitochondria induces the PTP. Since Complex I is one of the main sites of superoxide production in the cell [35], this experiment was carried out under conditions that maximize the activity of respiratory chain Complex I, i.e . in a buffer containing glutamate/malate.…”

Section: Resultsmentioning

confidence: 99%

SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

et al. 2013

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SERPINB3 (SB3) is a serine protease inhibitor overexpressed in several malignancies of epithelial origin, including primary liver cancer, where it inhibits apoptosis through poorly defined mechanisms. In the present study we analyze the effect of SB3 on hepatoma cell death elicited by a panel of chemotherapeutic agents. We report that SB3 shields cells from the toxicity of drugs with a pro-oxidant action such as doxorubicin, cisplatin and EM20-25. The rapid rise in ROS levels prompted by these compounds causes opening of the mitochondrial permeability transition pore (PTP), irreversibly committing cells to death. We find that a fraction of SB3 locates in mitochondrial inner compartments, and that this mitochondrial fraction increases under conditions of oxidative stress. Mitochondrial SB3 inhibits ROS generation and the ensuing PTP induction and cell death through an inhibitory interaction with respiratory Complex I. These findings identify a novel mechanism of action of SB3 that contributes to tumor cell resistance to anti-neoplastic drugs

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Section: Resultsmentioning

confidence: 99%

SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

et al. 2013

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“…Unfortunately, a sample from the mother could not be obtained. Subunit 1 is one of seven mtDNA encoded subunits included among the approximately 41 polypeptides of respiratory complex I [15]. Mutations in MT-ND1 cause a wide range of disorders, including Leber optic atrophy (OMIM #535000) [16,17], mitochondrial complex I deficiency (OMIM #252010) [18] and MELAS (OMIM #540000) [19].…”

Section: Resultsmentioning

confidence: 99%

Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

et al. 2013

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Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations.

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“…One of the most widely used neurotoxins is rotenone, which inhibits complex I in the mitochondrial oxidative phosphorylation pathway (12,13). Complex I inhibition results in a decrease in ATP synthesis and an accumulation of oxidative radicals, causing detrimental oxidative stress and cell death (13)(14)(15).…”

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confidence: 99%

Loss of Caspase-2-dependent Apoptosis Induces Autophagy after Mitochondrial Oxidative Stress in Primary Cultures of Young Adult Cortical Neurons

Tiwari

Lopez‐Cruzan

Morgan

et al. 2011

Journal of Biological Chemistry

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Mitochondrial dysfunctions have been associated with neuronal apoptosis and are characteristic of neurodegenerative conditions. Caspases play a central role in apoptosis; however, their involvement in mitochondrial dysfunction-induced neuronal apoptosis remains elusive. In the present report using rotenone, a complex I inhibitor that causes mitochondrial dysfunction, we determined the initiator caspase and its role in cell death in primary cultures of cortical neurons from young adult mice (1-2 months old). By pretreating the cells with a cell-permeable, biotinylated pan-caspase inhibitor that irreversibly binds to and traps the active caspase, we identified caspase-2 as an initiator caspase activated in rotenone-treated primary neurons. Loss of caspase-2 inhibited rotenone-induced apoptosis; however, these neurons underwent a delayed cell death by necrosis. We further found that caspase-2 acts upstream of mitochondria to mediate rotenone-induced apoptosis in neurons. The loss of caspase-2 significantly inhibited rotenone-induced activation of Bid and Bax and the release of cytochrome c and apoptosis inducing factor from mitochondria. Rotenone-induced downstream activation of caspase-3 and caspase-9 were also inhibited in the neurons lacking caspase-2. Autophagy was enhanced in caspase-2 knock-out neurons after rotenone treatment, and this response was important in prolonging neuronal survival. In summary, the present study identifies a novel function of caspase-2 in mitochondrial oxidative stress-induced apoptosis in neurons cultured from young adult mice.

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Mitochondrial Respiratory Complex I: Structure, Function and Implication in Human Diseases

Cited by 279 publications

References 146 publications

SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

Loss of Caspase-2-dependent Apoptosis Induces Autophagy after Mitochondrial Oxidative Stress in Primary Cultures of Young Adult Cortical Neurons

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