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Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.

TitleRedox-dependent loss of flavin by mitochondria complex I is different in brain and heart.
Publication TypeJournal Article
Year of Publication2022
AuthorsYoval-Sánchez B, Ansari F, James J, Niatsetskaya Z, Sosunov S, Filipenko P, Tikhonova IG, Ten V, Wittig I, Rafikov R, Galkin A
JournalRedox Biol
Volume51
Pagination102258
Date Published2022 Feb 06
ISSN2213-2317
Abstract

Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues.

DOI10.1016/j.redox.2022.102258
Alternate JournalRedox Biol
PubMed ID35189550
PubMed Central IDPMC8861397
Grant ListR01 HL132918 / HL / NHLBI NIH HHS / United States
R01 HL151447 / HL / NHLBI NIH HHS / United States
R01 NS100850 / NS / NINDS NIH HHS / United States
R01 NS112381 / NS / NINDS NIH HHS / United States