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

• Published in: Redox biology 2022-05, Vol.51, p.102258, Article 102258
• Main Authors: Yoval-Sánchez, Belem, Ansari, Fariha, James, Joel, Niatsetskaya, Zoya, Sosunov, Sergey, Filipenko, Peter, Tikhonova, Irina G., Ten, Vadim, Wittig, Ilka, Rafikov, Ruslan, Galkin, Alexander
• Format: Article
• Language: English
• Subjects: Brain; Brain - metabolism; Cardiac infarction; Dinitrocresols; Electron Transport Complex I - metabolism; Flavin mononucleotide; Flavin Mononucleotide - metabolism; Heart; Humans; Ischemia - metabolism; Isoforms; Mitochondria, Heart - metabolism; Mitochondrial complex I; Oxidation-Reduction; Research Paper; Reverse electron transfer; Stroke; Tissue-specificity
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2022.102258

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. [Display omitted] •Reverse electron transfer induces loss of complex I FMN in brain but not in heart.•Complex I content is higher in heart than in brain.•Kinetics of complex I FMN-dependent reactions is different in both tissues.•Long isoform of NDUFV3 subunit is present in the brain but not in the heart enzyme.•Molecular simulation predicts interaction of long isoform with FMN-binding site.