bims-misrem 2021-10-10 papers

Issue of 2021‒10‒10
three papers selected by
Rafael Antonio Casuso Pérez
University of Granada

J Cachexia Sarcopenia Muscle. 2021 Oct 03.

Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice.

Hyunjung Lee, Tae Youl Ha, Chang Hwa Jung, Farida Sukma Nirmala, So-Young Park, Yang Hoon Huh, Jiyun Ahn.

BACKGROUND: Although mounting evidence indicates that insulin resistance (IR) co-occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined.METHODS: Six-week-old C57BL/6 mice were fed a high-fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi-1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group).
RESULTS: Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (-37.8%, P < 0.01), ATP production (-88.0%, P < 0.01), mtDNA (-53.1%, P < 0.01), and mitochondrial respiration (-52.2% for maximal respiration, P < 0.05) in skeletal muscle but not in liver. Administration of mdivi-1 attenuated IR development by increasing mitochondrial function (+58.5% for mtDNA content, P < 0.01; 4.06 ± 0.69 to 5.84 ± 0.95 pmol/min/mg for citrate synthase activity, P < 0.05; 13.06 ± 0.70 to 34.87 ± 0.70 pmol/min/g for maximal respiration, P < 0.001). Western blot analysis showed acute IR resulted in increased autophagy (mitophagy) and UPRmt induction in muscle tissue. This adaptive response was inhibited by mdivi-1, which reduced the mitochondrial oxidative stress of skeletal muscle during acute IR.
CONCLUSIONS: Acute IR induced mitochondrial oxidative stress that impaired mitochondrial function in skeletal muscle. Improving mitochondrial function has important potential for treating acute IR.

Keywords: Insulin resistance; Mitochondria; Mitophagy; Oxidative stress; Skeletal muscle

DOI: https://doi.org/10.1002/jcsm.12794

Nat Rev Mol Cell Biol. 2021 Oct 07.

The assembly, regulation and function of the mitochondrial respiratory chain.

Irene Vercellino, Leonid A Sazanov.

The mitochondrial oxidative phosphorylation system is central to cellular metabolism. It comprises five enzymatic complexes and two mobile electron carriers that work in a mitochondrial respiratory chain. By coupling the oxidation of reducing equivalents coming into mitochondria to the generation and subsequent dissipation of a proton gradient across the inner mitochondrial membrane, this electron transport chain drives the production of ATP, which is then used as a primary energy carrier in virtually all cellular processes. Minimal perturbations of the respiratory chain activity are linked to diseases; therefore, it is necessary to understand how these complexes are assembled and regulated and how they function. In this Review, we outline the latest assembly models for each individual complex, and we also highlight the recent discoveries indicating that the formation of larger assemblies, known as respiratory supercomplexes, originates from the association of the intermediates of individual complexes. We then discuss how recent cryo-electron microscopy structures have been key to answering open questions on the function of the electron transport chain in mitochondrial respiration and how supercomplexes and other factors, including metabolites, can regulate the activity of the single complexes. When relevant, we discuss how these mechanisms contribute to physiology and outline their deregulation in human diseases.

DOI: https://doi.org/10.1038/s41580-021-00415-0

Elife. 2021 10 05. pii: e69207. [Epub ahead of print]10

Protective mitochondrial fission induced by stress-responsive protein GJA1-20k.

Daisuke Shimura, Esther Nuebel, Rachel Baum, Steven E Valdez, Shaohua Xiao, Junco S Warren, Joseph A Palatinus, TingTing Hong, Jared Rutter, Robin M Shaw.

The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.

Keywords: GJA1-20k; actin dynamics; cell biology; human; ischemia/reperfusion; mitochondria; mitochondria dynamics; mouse; organ protection

DOI: https://doi.org/10.7554/eLife.69207