Yoval-Sanchez 2022 Redox Biol

From Bioblast
Publications in the MiPMap
Yoval-SΓ‘nchez B, Ansari F, James J, Niatsetskaya Z, Sosunov S, Filipenko P, Tikhonova IG, Ten V, Wittig I, Rafikov R, Galkin A (2022) Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart. https://doi.org/10.1016/j.redox.2022.102258

Β» Redox Biol 51:102258. PMID: 35189550 Open Access

Yoval-Sanchez Belem,  Ansari Fariha,  James Joel,  Niatsetskaya Zoya,  Sosunov Sergey,  Filipenko Peter,  Tikhonova Irina G,  Ten Vadim,  Wittig Ilka,  Rafikov Ruslan,  Galkin Alexander (2022) Redox Biol

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. β€’ Keywords: Brain, Cardiac infarction, Flavin mononucleotide, Heart, Isoforms, Mitochondrial complex I, Reverse electron transfer, Stroke, Tissue-specificity β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: DE Frankfurt Wittig I, US NY New York Galkin A

Labels: MiParea: Respiration 

Stress:Ischemia-reperfusion  Organism: Mouse  Tissue;cell: Heart, Nervous system  Preparation: Isolated mitochondria  Enzyme: Complex I 

Coupling state: LEAK, OXPHOS  Pathway: NS  HRR: Oxygraph-2k, O2k-Fluorometer 

2022-12, AmR 

Cookies help us deliver our services. By using our services, you agree to our use of cookies.