bims-resufa 2022-02-27 papers

Issue of 2022‒02‒27
two papers selected by
Vera Strogolova
Strong Microbials, Inc

Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2110357119. [Epub ahead of print]119(9):

Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly.

Luke E Formosa, Shadi Maghool, Alice J Sharpe, Boris Reljic, Linden Muellner-Wong, David A Stroud, Michael T Ryan, Megan J Maher.

Cytochrome c oxidase (COX) assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia, and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here, we show that loss of COA7 blocks complex IV assembly after the initial step where the COX1 module is built, progression from which requires the incorporation of copper and addition of the COX2 and COX3 modules. The crystal structure of COA7, determined to 2.4 Å resolution, reveals a banana-shaped molecule composed of five helix-turn-helix (α/α) repeats, tethered by disulfide bonds. COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 and catalyzes the reduction of disulfide bonds within these proteins, which are crucial for copper relay to COX2. COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. We therefore propose that COA7 is a heme-binding disulfide reductase for regenerating the copper relay system that underpins complex IV assembly.

Keywords: COA7; X-ray crystallography; cytochrome c oxidase; heme; mitochondria

DOI: https://doi.org/10.1073/pnas.2110357119

J Exp Biol. 2022 Feb 15. pii: jeb196725. [Epub ahead of print]225(4):

Adaptations to a hypoxic lifestyle in naked mole-rats.

Matthew E Pamenter.

Hypoxia is one of the strongest environmental drivers of cellular and physiological adaptation. Although most mammals are largely intolerant of hypoxia, some specialized species have evolved mitigative strategies to tolerate hypoxic niches. Among the most hypoxia-tolerant mammals are naked mole-rats (Heterocephalus glaber), a eusocial species of subterranean rodent native to eastern Africa. In hypoxia, naked mole-rats maintain consciousness and remain active despite a robust and rapid suppression of metabolic rate, which is mediated by numerous behavioural, physiological and cellular strategies. Conversely, hypoxia-intolerant mammals and most other hypoxia-tolerant mammals cannot achieve the same degree of metabolic savings while staying active in hypoxia and must also increase oxygen supply to tissues, and/or enter torpor. Intriguingly, recent studies suggest that naked mole-rats share many cellular strategies with non-mammalian vertebrate champions of anoxia tolerance, including the use of alternative metabolic end-products and potent pH buffering mechanisms to mitigate cellular acidification due to upregulation of anaerobic metabolic pathways, rapid mitochondrial remodelling to favour increased respiratory efficiency, and systemic shifts in energy prioritization to maintain brain function over that of other tissues. Herein, I discuss what is known regarding adaptations of naked mole-rats to a hypoxic lifestyle, and contrast strategies employed by this species to those of hypoxia-intolerant mammals, closely related African mole-rats, other well-studied hypoxia-tolerant mammals, and non-mammalian vertebrate champions of anoxia tolerance. I also discuss the neotenic theory of hypoxia tolerance - a leading theory that may explain the evolutionary origins of hypoxia tolerance in mammals - and highlight promising but underexplored avenues of hypoxia-related research in this fascinating model organism.

Keywords: Glycolysis; Heterotherm; Hypoxia; Hypoxic metabolic response; Hypoxic ventilatory response; Ischaemia; Mammals; Metabolic rate suppression; Mitochondria; Thermoregulation

DOI: https://doi.org/10.1242/jeb.196725