bims-cytox1 2020-04-12 papers

Issue of 2020‒04‒12
five papers selected by
Gavin McStay
Staffordshire University

Biochim Biophys Acta Bioenerg. 2020 Apr 07. pii: S0005-2728(20)30052-9. [Epub ahead of print] 148202

TMEM70 functions in the assembly of complexes I and V.

Laura Sánchez-Caballero, Dei M Elurbe, Fabian Baertling, Sergio Guerrero-Castillo, Mariel van den Brand, Joeri van Strien, Teunis J P van Dam, Richard Rodenburg, Ulrich Brandt, Martijn A Huynen, Leo G J Nijtmans.

Protein complexes from the oxidative phosphorylation (OXPHOS) system are assembled with the help of proteins called assembly factors. We here delineate the function of the inner mitochondrial membrane protein TMEM70, in which mutations have been linked to OXPHOS deficiencies, using a combination of BioID, complexome profiling and coevolution analyses. TMEM70 interacts with complex I and V and for both complexes the loss of TMEM70 results in the accumulation of an assembly intermediate followed by a reduction of the next assembly intermediate in the pathway. This indicates that TMEM70 has a role in the stability of membrane-bound subassemblies or in the membrane recruitment of subunits into the forming complex. Independent evidence for a role of TMEM70 in OXPHOS assembly comes from evolutionary analyses. The TMEM70/TMEM186/TMEM223 protein family, of which we show that TMEM186 and TMEM223 are mitochondrial in human as well, only occurs in species with OXPHOS complexes. Our results validate the use of combining complexome profiling with BioID and evolutionary analyses in elucidating congenital defects in protein complex assembly.

Keywords: Assembly factor; Complex I; Complex V; Oxidative phosphorylation

DOI: https://doi.org/10.1016/j.bbabio.2020.148202

Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(20)30008-3. [Epub ahead of print]351 101-148

Type 3 IP3 receptors: The chameleon in cancer.

Nicolas Rosa, Flore Sneyers, Jan B Parys, Geert Bultynck.

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), intracellular calcium (Ca2+) release channels, fulfill key functions in cell death and survival processes, whose dysregulation contributes to oncogenesis. This is essentially due to the presence of IP3Rs in microdomains of the endoplasmic reticulum (ER) in close proximity to the mitochondria. As such, IP3Rs enable efficient Ca2+ transfers from the ER to the mitochondria, thus regulating metabolism and cell fate. This review focuses on one of the three IP3R isoforms, the type 3 IP3R (IP3R3), which is linked to proapoptotic ER-mitochondrial Ca2+ transfers. Alterations in IP3R3 expression have been highlighted in numerous cancer types, leading to dysregulations of Ca2+ signaling and cellular functions. However, the outcome of IP3R3-mediated Ca2+ transfers for mitochondrial function is complex with opposing effects on oncogenesis. IP3R3 can either suppress cancer by promoting cell death and cellular senescence or support cancer by driving metabolism, anabolic processes, cell cycle progression, proliferation and invasion. The aim of this review is to provide an overview of IP3R3 dysregulations in cancer and describe how such dysregulations alter critical cellular processes such as proliferation or cell death and survival. Here, we pose that the IP3R3 isoform is not only linked to proapoptotic ER-mitochondrial Ca2+ transfers but might also be involved in prosurvival signaling.

Keywords: Apoptosis; Calcium signaling; Cancer; Cell death; Cell survival; Expression; ITPR3; Inositol 1,4,5-trisphosphate receptors; Modulation; Oncogenesis; Tumor suppressor

DOI: https://doi.org/10.1016/bs.ircmb.2020.02.003

Nat Commun. 2020 Apr 08. 11(1): 1740

Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans.

Wei Wei, Alistair T Pagnamenta, Nicholas Gleadall, Alba Sanchis-Juan, Jonathan Stephens, John Broxholme, Salih Tuna, Christopher A Odhams, , , Carl Fratter, Ernest Turro, Mark J Caulfield, Jenny C Taylor, Shamima Rahman, Patrick F Chinnery.

Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.

DOI: https://doi.org/10.1038/s41467-020-15336-3

Front Mol Neurosci. 2020 ;13 43

Interference With Complex IV as a Model of Age-Related Decline in Synaptic Connectivity.

Martin Kriebel, Julia Ebel, Florian Battke, Stefan Griesbach, Hansjürgen Volkmer.

Age-related impairment of mitochondrial function may negatively impact energy-demanding processes such as synaptic transmission thereby triggering cognitive decline and processes of neurodegeneration. Here, we present a novel model for age-related mitochondrial impairment based on partial inhibition of cytochrome c oxidase subunit 4 (Cox4) of complex IV of the respiratory chain. miRNA-mediated knockdown of Cox4 correlated with a marked reduction in excitatory and inhibitory synaptic marker densities in vitro and in vivo as well as an impairment of neuronal network activity in primary neuronal cultures. Transcriptome analysis identified the deregulation of gene clusters, which link induced mitochondrial perturbation to impaired synaptic function and plasticity as well as processes of aging. In conclusion, the model of Cox4 deficiency reflects aspects of age-related dementia and might, therefore, serve as a novel test system for drug development.

Keywords: Cox4; aging; cytochrome c oxidase; mitochondria; neurodegeneration; synaptic connectivity

DOI: https://doi.org/10.3389/fnmol.2020.00043

Cell Metab. 2020 Apr 07. pii: S1550-4131(20)30126-1. [Epub ahead of print]31(4): 669-678

Systems Biochemistry Approaches to Defining Mitochondrial Protein Function.

Andrew Y Sung, Brendan J Floyd, David J Pagliarini.

Defining functions for the full complement of proteins is a grand challenge in the post-genomic era and is essential for our understanding of basic biology and disease pathogenesis. In recent times, this endeavor has benefitted from a combination of modern large-scale and classical reductionist approaches-a process we refer to as "systems biochemistry"-that helps surmount traditional barriers to the characterization of poorly understood proteins. This strategy is proving to be particularly effective for mitochondria, whose well-defined proteome has enabled comprehensive analyses of the full mitochondrial system that can position understudied proteins for fruitful mechanistic investigations. Recent systems biochemistry approaches have accelerated the identification of new disease-related mitochondrial proteins and of long-sought "missing" proteins that fulfill key functions. Collectively, these studies are moving us toward a more complete understanding of mitochondrial activities and providing a molecular framework for the investigation of mitochondrial pathogenesis.

Keywords: mitochondria; multi-omics; orphan proteins; rare disease; systems biochemistry

DOI: https://doi.org/10.1016/j.cmet.2020.03.011