bims-cytox1 2019-05-26 papers

Issue of 2019–05–26
five papers selected by
Gavin McStay, Staffordshire University

Redox Biol. 2019 May 09. pii: S2213-2317(19)30194-6. [Epub ahead of print]24 101214

Cholesterol enrichment in liver mitochondria impairs oxidative phosphorylation and disrupts the assembly of respiratory supercomplexes.

Estel Solsona-Vilarrasa, Raquel Fucho, Sandra Torres, Susana Nuñez, Natalia Nuño-Lámbarri, Carlos Enrich, Carmen García-Ruiz, José C Fernández-Checa.

Mitochondrial cholesterol accumulation is a hallmark of alcoholic and non-alcoholic fatty liver diseases and impairs the function of specific solute carriers through changes in membrane physical properties. However, its impact on mitochondrial respiration and organization of respiratory supercomplexes has not been determined so far. Here we fed mice a cholesterol-enriched diet (HC) supplemented with sodium cholate to examine the effect of cholesterol in mitochondrial function. HC feeding increased liver cholesterol content, which downregulated Srebp2 and Hmgcr expression, while sodium cholate administration decreased Cyp7a1 and Cyp8b1 mRNA levels, suggesting the downregulation of bile acid synthesis through the classical pathway. HC-fed mice exhibited increased expression of Stard1 and Mln64 and enhanced mitochondrial free cholesterol levels (2-3 fold), leading to decreased membrane fluidity. Mitochondria from HC-fed mice displayed increased cholesterol loading in both outer and inner mitochondrial membranes. Cholesterol loading decreased complex I and complex II-driven state 3 respiration and mitochondrial membrane potential. Decreased respiratory and uncoupling control ratio from complex I was also observed after in situ enrichment of mouse liver mitochondria with cholesterol or enantiomer cholesterol, the mirror image of natural cholesterol. Moreover, in vivo cholesterol loading decreased the level of complex III2 and the assembly of respiratory supercomplexes I1+III2+IV and I1+III2. Moreover, HC feeding caused oxidative stress and mitochondrial GSH (mGSH) depletion, which translated in hepatic steatosis and liver injury, effects that were rescued by replenishing mGSH with GSH ethyl ester. Overall, mitochondrial cholesterol accumulation disrupts mitochondrial functional performance and the organization of respiratory supercomplexes assembly, which can contribute to oxidative stress and liver injury.

Keywords: Cholesterol; Hepatic diseases; Liver; Mitochondria; Oxidative stress; Respiration

DOI: https://doi.org/10.1016/j.redox.2019.101214

Sci Rep. 2019 May 21. 9(1): 7637

Role of the membrane potential in mitochondrial protein unfolding and import.

Takehiro K Sato, Shin Kawano, Toshiya Endo.

Newly synthesized mitochondrial precursor proteins have to become unfolded to cross the mitochondrial membranes. This unfolding is achieved primarily by mitochondrial Hsp70 (mtHsp70) for presequence-containing precursor proteins. However, the membrane potential across the inner membrane (ΔΨ) could also contribute to unfolding of short-presequence containing mitochondrial precursor proteins. Here we investigated the role of ΔΨ in mitochondrial protein unfolding and import. We found that the effects of mutations in the presequence on import rates are correlated well with the hydrophobicity or ability to interact with import motor components including mtHsp70, but not with ΔΨ (negative inside). A spontaneously unfolded precursor protein with a short presequence is therefore trapped by motor components including mtHsp70, but not ΔΨ, which could cause global unfolding of the precursor protein. Instead, ΔΨ may contribute the precursor unfolding by holding the presequence at the inner membrane for trapping of the unfolded species by the import motor system.

DOI: https://doi.org/10.1038/s41598-019-44152-z

Nature. 2019 May 22.

Mitochondrial protein translocation-associated degradation.

Christoph U Mårtensson, Chantal Priesnitz, Jiyao Song, Lars Ellenrieder, Kim Nguyen Doan, Felix Boos, Alessia Floerchinger, Nicole Zufall, Silke Oeljeklaus, Bettina Warscheid, Thomas Becker.

Mitochondrial biogenesis and functions depend on the import of precursor proteins via the 'translocase of the outer membrane' (TOM complex). Defects in protein import lead to an accumulation of mitochondrial precursor proteins that induces a range of cellular stress responses. However, constitutive quality-control mechanisms that clear trapped precursor proteins from the TOM channel under non-stress conditions have remained unknown. Here we report that in Saccharomyces cerevisiae Ubx2, which functions in endoplasmic reticulum-associated degradation, is crucial for this quality-control process. A pool of Ubx2 binds to the TOM complex to recruit the AAA ATPase Cdc48 for removal of arrested precursor proteins from the TOM channel. This mitochondrial protein translocation-associated degradation (mitoTAD) pathway continuously monitors the TOM complex under non-stress conditions to prevent clogging of the TOM channel with precursor proteins. The mitoTAD pathway ensures that mitochondria maintain their full protein-import capacity, and protects cells against proteotoxic stress induced by impaired transport of proteins into mitochondria.

DOI: https://doi.org/10.1038/s41586-019-1227-y

Proc Natl Acad Sci U S A. 2019 May 20. pii: 201900890. [Epub ahead of print]

Assembly of the complexes of oxidative phosphorylation triggers the remodeling of cardiolipin.

Yang Xu, Murari Anjaneyulu, Alec Donelian, Wenxi Yu, Miriam L Greenberg, Mindong Ren, Edward Owusu-Ansah, Michael Schlame.

Cardiolipin (CL) is a mitochondrial phospholipid with a very specific and functionally important fatty acid composition, generated by tafazzin. However, in vitro tafazzin catalyzes a promiscuous acyl exchange that acquires specificity only in response to perturbations of the physical state of lipids. To identify the process that imposes acyl specificity onto CL remodeling in vivo, we analyzed a series of deletions and knockdowns in Saccharomyces cerevisiae and Drosophila melanogaster, including carriers, membrane homeostasis proteins, fission-fusion proteins, cristae-shape controlling and MICOS proteins, and the complexes I-V. Among those, only the complexes of oxidative phosphorylation (OXPHOS) affected the CL composition. Rather than any specific complex, it was the global impairment of the OXPHOS system that altered CL and at the same time shortened its half-life. The knockdown of OXPHOS expression had the same effect on CL as the knockdown of tafazzin in Drosophila flight muscles, including a change in CL composition and the accumulation of monolyso-CL. Thus, the assembly of OXPHOS complexes induces CL remodeling, which, in turn, leads to CL stabilization. We hypothesize that protein crowding in the OXPHOS system imposes packing stress on the lipid bilayer, which is relieved by CL remodeling to form tightly packed lipid-protein complexes.

Keywords: cardiolipin; lipids; membrane; mitochondria; respiration

DOI: https://doi.org/10.1073/pnas.1900890116

Science. 2019 May 24. pii: eaau6520. [Epub ahead of print]364(6442):

Germline selection shapes human mitochondrial DNA diversity.

NIHR BioResource–Rare Diseases

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.

DOI: https://doi.org/10.1126/science.aau6520