bims-misrem 2021-10-31 papers

Int J Biochem Cell Biol. 2021 Oct 22. pii: S1357-2725(21)00182-5. [Epub ahead of print] 106101

It takes two to tango; the essential role of ER-mitochondrial contact sites in mitochondrial dynamics.

Irene M G M Hemel, Rita Sarantidou, Mike Gerards.

Mitochondria change their shape, size and number, in response to cellular demand, through mitochondrial dynamics. The interaction between mitochondria and the ER, through ER-mitochondrial contact sites, is crucial in mitochondrial dynamics. Several protein complexes tethering mitochondria to the ER include proteins involved in fission or fusion but also proteins involved in calcium homeostasis, which is known to affect mitochondrial dynamics. The formation of these contact sites are especially important for mitochondrial fission as these contact sites induce both outer and inner membrane constriction, prior to recruitment of Drp1. While the exact molecular mechanisms behind these constrictions remain uncertain, several hypotheses have been proposed. In this review, we discuss the involvement of tethering complexes in mitochondrial dynamics and provide an overview of the current knowledge and hypotheses on the constriction of the outer and inner mitochondrial membrane at ER-mitochondrial contact sites.

Keywords: ER-mitochondrial contact; Mitochondrial dynamics; Mitochondrial membrane constriction

DOI: https://doi.org/10.1016/j.biocel.2021.106101

Exerc Sport Sci Rev. 2021 Oct 22.

The HO-1/CO System and Mitochondrial Quality Control in Skeletal Muscle.

Heath G Gasier, Hagir B Suliman, Claude A Piantadosi.

ABSTRACT: Inducible heme oxygenase (HO)-1 catalyzes the breakdown of heme to biliverdin, iron and carbon monoxide (CO). CO binds to cytochrome c oxidase and alters mitochondrial redox balance and coordinately regulates mitochondrial quality control (MQC) during oxidant stress and inflammation. The hypothesis presented is that skeletal muscle HO-1/CO system helps modulate components in the MQC cycle during metabolic stress.

DOI: https://doi.org/10.1249/JES.0000000000000277

Physiol Rev. 2021 10 26.

Mitochondrial calcium exchange in physiology and disease.

Joanne F Garbincius, John W Elrod.

The uptake of calcium into and extrusion of calcium from the mitochondrial matrix is a fundamental biological process that has critical effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium (mCa2+) cycling is implicated in numerous acquired diseases such as heart failure, stroke, neurodegeneration, diabetes, and cancer, and is genetically linked to several inherited neuromuscular disorders. Understanding the mechanisms responsible for mCa2+ exchange therefore holds great promise for the treatment of these diseases. The past decade has seen the genetic identification of many of the key proteins that mediate mitochondrial calcium uptake and efflux. Here, we present an overview of the phenomenon of mCa2+ transport, and a comprehensive examination of the molecular machinery that mediates calcium flux across the inner mitochondrial membrane: the mitochondrial uniporter complex (consisting of MCU, EMRE, MICU1, MICU2, MICU3, MCUB, and MCUR1), NCLX, LETM1, the mitochondrial ryanodine receptor, and the mitochondrial permeability transition pore. We then consider the physiological implications of mCa2+ flux and evaluate how alterations in mCa2+ homeostasis contribute to human disease. This review concludes by highlighting opportunities and challenges for therapeutic intervention in pathologies characterized by aberrant mCa2+ handling and by summarizing critical unanswered questions regarding the biology of mCa2+ flux.

Keywords: calcium; energetics; metabolism; mitochondria; oxidative phosphorylation

DOI: https://doi.org/10.1152/physrev.00041.2020

Dev Cell. 2021 Oct 22. pii: S1534-5807(21)00809-1. [Epub ahead of print]

Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain.

Shefali Krishna, Rafael Arrojo E Drigo, Juliana S Capitanio, Ranjan Ramachandra, Mark Ellisman, Martin W Hetzer.

In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.

Keywords: age mosaicism; aging; electron transport chain; heterogeneity; long-lived proteins; mitochondria; muscle; neurons; protein homeostasis; supercomplexes

DOI: https://doi.org/10.1016/j.devcel.2021.10.008

FEBS J. 2021 Oct 28.

The mitochondrial permeability transition: Recent progress and open questions.

Paolo Bernardi, Michela Carraro, Giovanna Lippe.

Major progress has been made in defining the basis of the mitochondrial permeability transition, a Ca2+ -dependent permeability increase of the inner membrane that has puzzled mitochondrial research for almost 70 years. Initially considered an artifact of limited biological interest by most, over the years the permeability transition has raised to the status of regulator of mitochondrial ion homeostasis and of druggable effector mechanism of cell death. The permeability transition is mediated by opening of channel(s) modulated by matrix cyclophilin D, the permeability transition pore(s) (PTP). The field has received new impulse (i) from the hypothesis that the PTP may originate from a Ca2+ -dependent conformational change of F-ATP synthase; and (ii) from the reevaluation of the long-standing hypothesis that it originates from the adenine nucleotide translocator (ANT). Here, we provide a synthetic account of the structure of ANT and F-ATP synthase in order to discuss potential and controversial mechanisms through which they may form high-conductance channels; and review some intriguing findings from the wealth of early studies of PTP modulation that still await an explanation. We hope that this review will stimulate new experiments addressing the many outstanding problems, and thus contribute to the eventual solution of the puzzle of the permeability transition.

Keywords: ATP synthase; Mitochondria; adenine nucleotide translocator; calcium transport; channels; cyclophilin; cyclosporin; permeability transition

DOI: https://doi.org/10.1111/febs.16254