bims-cytox1 2020-09-20 papers

Issue of 2020–09–20
four papers selected by
Gavin McStay, Staffordshire University

Int J Mol Sci. 2020 Sep 12. pii: E6683. [Epub ahead of print]21(18):

Mechanisms Underlying the Regulation of Mitochondrial Respiratory Chain Complexes by Nuclear Steroid Receptors.

Ami Kobayashi, Kotaro Azuma, Kazuhiro Ikeda, Satoshi Inoue.

Mitochondrial respiratory chain complexes play important roles in energy production via oxidative phosphorylation (OXPHOS) to drive various biochemical processes in eukaryotic cells. These processes require coordination with other cell organelles, especially the nucleus. Factors encoded by both nuclear and mitochondrial DNA are involved in the formation of active respiratory chain complexes and 'supercomplexes', the higher-order structures comprising several respiratory chain complexes. Various nuclear hormone receptors are involved in the regulation of OXPHOS-related genes. In this article, we review the roles of nuclear steroid receptors (NR3 class nuclear receptors), including estrogen receptors (ERs), estrogen-related receptors (ERRs), glucocorticoid receptors (GRs), mineralocorticoid receptors (MRs), progesterone receptors (PRs), and androgen receptors (ARs), in the regulatory mechanisms of mitochondrial respiratory chain complex and supercomplex formation.

Keywords: NR3 class nuclear receptor; mitochondria; nuclear receptor; nuclear steroid receptor; oxidative phosphorylation (OXPHOS); respiratory chain complex; respiratory chain supercomplex

DOI: https://doi.org/10.3390/ijms21186683

Sci Adv. 2020 Jul;pii: eaba5345. [Epub ahead of print]6(31):

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics.

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.

DOI: https://doi.org/10.1126/sciadv.aba5345

Sci Rep. 2020 Sep 18. 10(1): 15336

Decoding mitochondrial heterogeneity in single muscle fibres by imaging mass cytometry.

Charlotte Warren, David McDonald, Roderick Capaldi, David Deehan, Robert W Taylor, Andrew Filby, Doug M Turnbull, Conor Lawless, Amy E Vincent.

The study of skeletal muscle continues to support the accurate diagnosis of mitochondrial disease and remains important in delineating molecular disease mechanisms. The heterogeneous expression of oxidative phosphorylation proteins and resulting respiratory deficiency are both characteristic findings in mitochondrial disease, hence the rigorous assessment of these at a single cell level is incredibly powerful. Currently, the number of proteins that can be assessed in individual fibres from a single section by immunohistochemistry is limited but imaging mass cytometry (IMC) enables the quantification of further, discrete proteins in individual cells. We have developed a novel workflow and bespoke analysis for applying IMC in skeletal muscle biopsies from patients with genetically-characterised mitochondrial disease, investigating the distribution of nine mitochondrial proteins in thousands of single muscle fibres. Using a semi-automated analysis pipeline, we demonstrate the accurate quantification of protein levels using IMC, providing an accurate measure of oxidative phosphorylation deficiency for complexes I-V at the single cell level. We demonstrate signatures of oxidative phosphorylation deficiency for common mtDNA variants and nuclear-encoded complex I variants and a compensatory upregulation of unaffected oxidative phosphorylation components. This technique can now be universally applied to evaluate a wide range of skeletal muscle disorders and protein targets.

DOI: https://doi.org/10.1038/s41598-020-70885-3

Sci Adv. 2020 Aug;6(35): eabb0780

Cardiolipin, conformation, and respiratory complex-dependent oligomerization of the major mitochondrial ADP/ATP carrier in yeast.

N Senoo, S Kandasamy, O B Ogunbona, M G Baile, Y Lu, S M Claypool.

The phospholipid cardiolipin has pleiotropic structural and functional roles that are collectively essential for mitochondrial biology. Yet, the molecular details of how this lipid supports the structure and function of proteins and protein complexes are poorly understood. To address this property of cardiolipin, we use the mitochondrial adenosine 5'-diphosphate/adenosine 5'-triphosphate carrier (Aac) as a model. Here, we have determined that cardiolipin is critical for both the tertiary and quaternary assembly of the major yeast Aac isoform Aac2 as well as its conformation. Notably, these cardiolipin-provided structural roles are separable. In addition, we show that multiple copies of Aac2 engage in shared complexes that are largely dependent on the presence of assembled respiratory complexes III and IV or respiratory supercomplexes. Intriguingly, the assembly state of Aac2 is sensitive to its transport-related conformation. Together, these results expand our understanding of the numerous structural roles provided by cardiolipin for mitochondrial membrane proteins.

DOI: https://doi.org/10.1126/sciadv.abb0780