bims-cytox1 2019-10-27 papers

Issue of 2019–10–27
three papers selected by
Gavin McStay, Staffordshire University

FASEB J. 2019 Oct 24. fj201900708R

Sirt3-dependent deacetylation of COX-1 counteracts oxidative stress-induced cell apoptosis.

Long-Fang Tu, Ling-Fang Cao, Yue-Hong Zhang, Yu-Lin Guo, Yang-Fan Zhou, Wei-Qi Lu, Tian-Ze Zhang, Tao Zhang, Gao-Xiao Zhang, Hiroshi Kurihara, Yi-Fang Li, Rong-Rong He.

The mitochondrial complexes are prone to sirtuin (Sirt)3-mediated deacetylation modification, which may determine cellular response to stimuli, such as oxidative stress. In this study, we show that the cytochrome c oxidase (COX)-1, a core catalytic subunit of mitochondrial complex IV, was acetylated and deactivated both in 2,2'-azobis(2-amidinopropane) dihydrochloride-treated NIH/3T3 cells and hydrogen peroxide-treated primary neuronal cells, correlating with apoptotic cell death induction by oxidative stress. Inhibition of Sirt3 by small interfering RNA or the inhibitor nicotinamide induced accumulation of acetylation of COX-1, reduced mitochondrial membrane potential, and increased cell apoptosis. In contrast, overexpression of Sirt3 enhanced deacetylation of COX-1 and inhibited oxidative stress-induced apoptotic cell death. Significantly, rats treated with ischemia/reperfusion injury, a typical oxidative stress-related disease, presented an inhibition of Sirt3-induced hyperacetylation of COX-1 in the brain tissues. Furthermore, K13, K264, K319, and K481 were identified as the acetylation sits of COX-1 in response to oxidative stress. In conclusion, COX-1 was discovered as a new deacetylation target of Sirt3, indicating that the Sirt3/COX-1 axis is a promising therapy target of stress-related diseases.-Tu, L.-F., Cao, L.-F., Zhang, Y.-H., Guo, Y.-L., Zhou, Y.-F., Lu, W.-Q., Zhang, T.-Z., Zhang, T., Zhang, G.-X., Kurihara, H., Li, Y.-F., He, R.-R. Sirt3-dependent deacetylation of COX-1 counteracts oxidative stress-induced cell apoptosis.

Keywords: ROS; cytochrome c oxidase; mitochondria

DOI: https://doi.org/10.1096/fj.201900708R

Mol Genet Metab. 2019 Sep 14. pii: S1096-7192(19)30530-X. [Epub ahead of print]

Resolving complexity in mitochondrial disease: Towards precision medicine.

Róisín M Boggan, Albert Lim, Robert W Taylor, Robert McFarland, Sarah J Pickett.

Mitochondrial diseases, caused by mutations in either the nuclear or mitochondrial genomes (mtDNA), are the most common form of inherited neurometabolic disorders. They are remarkably heterogeneous, both in their clinical presentation and genetic etiology, presenting challenges for diagnosis, clinical management and elucidation of molecular mechanism. The multifaceted nature of these diseases, compounded by the unique characteristics of mitochondrial genetics, cement their space in the field of complex disease. In this review we examine the m.3243A>G variant, one of the most prevalent mitochondrial DNA mutations, using it as an exemplar to demonstrate the challenges presented by these complex disorders. Disease caused by m.3243A>G is one of the most phenotypically diverse of all mitochondrial diseases; we outline known causes of this heterogeneity including mtDNA heteroplasmy, mtDNA copy number and nuclear genetic factors. We consider the impact that this has in the clinic, discussing the personalized management of common manifestations attributed to this pathogenic mtDNA variant, including hearing impairment, diabetes mellitus, myopathy, cardiac disease, stroke-like episodes and gastrointestinal disturbances. Future research into this complex disorder must account for this heterogeneity, benefitting from the use of large patient cohorts to build upon current clinical expertise. Through multi-disciplinary collaboration, the complexities of this mitochondrial disease can be addressed with the variety of diagnostic, prognostic, and treatment approaches that are moulded to best fit the needs of each individual patient.

Keywords: Complex disease; Heterogeneity; MELAS; Mitochondrial disease; Precision medicine; m.3243A>G

DOI: https://doi.org/10.1016/j.ymgme.2019.09.003

FASEB J. 2019 Oct 25. fj201900685RR

TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme.

Jana Kovalčíková, Marek Vrbacký, Petr Pecina, Kateřina Tauchmannová, Hana Nůsková, Vilma Kaplanová, Andrea Brázdová, Lukáš Alán, Jan Eliáš, Kristýna Čunátová, Vladimír Kořínek, Radislav Sedlacek, Tomáš Mráček, Josef Houštěk.

Biogenesis of F1Fo ATP synthase, the key enzyme of mitochondrial energy provision, depends on transmembrane protein 70 (TMEM70), localized in the inner mitochondrial membrane of higher eukaryotes. TMEM70 absence causes severe ATP-synthase deficiency and leads to a neonatal mitochondrial encephalocardiomyopathy in humans. However, the exact biochemical function of TMEM70 remains unknown. Using TMEM70 conditional knockout in mice, we show that absence of TMEM70 impairs the early stage of enzyme biogenesis by preventing incorporation of hydrophobic subunit c into rotor structure of the enzyme. This results in the formation of an incomplete, pathologic enzyme complex consisting of F1 domain and peripheral stalk but lacking Fo proton channel composed of subunits c and a. We demonstrated direct interaction between TMEM70 and subunit c and showed that overexpression of subunit c in TMEM70-/- cells partially rescued TMEM70 defect. Accordingly, TMEM70 knockdown prevented subunit c accumulation otherwise observed in F1-deficient cells. Altogether, we identified TMEM70 as specific ancillary factor for subunit c. The biologic role of TMEM70 is to increase the low efficacy of spontaneous assembly of subunit c oligomer, the key and rate-limiting step of ATP-synthase biogenesis, and thus to reach an adequately high physiologic level of ATP synthase in mammalian tissues.-Kovalčíková, J., Vrbacký, M., Pecina, P., Tauchmannová, K., Nůsková, H., Kaplanová, V., Brázdová, A., Alán, L., Eliáš, J., Čunátová, K., Kořínek, V., Sedlacek, R., Mráček, T., Houštěk, J. TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme.

Keywords: ATP5G assembly; ancillary factor; mitochondria; mouse knockout

DOI: https://doi.org/10.1096/fj.201900685RR