bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2021‒08‒22
five papers selected by
Gavin McStay
Staffordshire University

  1. Mol Cell Biol. 2021 Aug 16. MCB0023321
      Mitochondrial oxidative phosphorylation (OXPHOS) enzymes are made up of dual genetic origin. Mechanisms regulating the expression of nuclear-encoded OXPHOS subunits in response to metabolic cues (glucose vs. glycerol), is significantly understood while regulation of mitochondrially encoded OXPHOS subunits is poorly defined. Here, we show that IRC3 a DEAD/H box helicase, previously implicated in mitochondrial DNA maintenance, is central to integrating metabolic cues with mitochondrial translation. Irc3 associates with mitochondrial small ribosomal subunit in cells consistent with its role in regulating translation elongation based on Arg8m reporter system. IRC3 deleted cells retained mitochondrial DNA despite growth defect on glycerol plates. Glucose grown Δirc3ρ+ and irc3 temperature-sensitive cells at 370C have reduced translation rates from majority of mRNAs. In contrast, when galactose was the carbon source, reduction in mitochondrial translation was observed predominantly from Cox1 mRNA in Δirc3ρ+ but no defect was observed in irc3 temperature-sensitive cells, at 370C. In support, of a model whereby IRC3 responds to metabolic cues to regulate mitochondrial translation, suppressors of Δirc3 isolated for restoration of growth on glycerol media restore mitochondrial protein synthesis differentially in presence of glucose vs. glycerol.
  2. Mitochondrion. 2021 Aug 11. pii: S1567-7249(21)00108-2. [Epub ahead of print]
      INTRODUCTION: Isolated complex I deficiency causes several clinical syndromes, including Leigh syndrome (LS), Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Here we reported two new patients carrying the rare m.3890G>A/MT-ND1 (p.Arg195Gln) mitochondrial DNA (mtDNA) pathogenic variant, revisited another two previously reported cases, and reviewed the remaining published cases, to refine the clinical and neuroimaging features. We also quantitatively assessed the mtDNA heteroplasmy in all available tissues.CASES PRESENTATION: The first patient was a 25-year-old male presenting with axonal polyneuropathy, optic atrophy consistent with LHON, gaze palsy and parkinsonism. MRI correlates included transient centromedullary T2 hyperintensity in the conus medullaris, transient signal intensity and increased lactate in the midbrain periaqueductal gray matter, and late atrophy of the optic nerves and chiasm, dorsal midbrain and conus medullaris. The second patient was a 65-year-old woman with a classical LHON phenotype and a normal MRI.
    DISCUSSION: Including the previously published cases, the clinical spectrum ranged from LHON to Leigh-like syndrome with peculiar CNS lesions and encephalopatic clinical symptoms. The most severe and complex cases were associated with very high heteroplasmy, or nearly homoplasmic m.3890G>A/MT-ND1 pathogenic variant in skeletal muscle, displaying neurological symptoms/signs consistent with Leigh-like lesions on brain MRI. Lower heteroplasmic mutational loads were instead associated with isolated LHON-like optic neuropathy of variable severity.
    CONCLUSION: The m.3890G>A/MT-ND1 mtDNA pathogenic variant increasingly impairs complex I function dependent on heteroplasmic loads, leading to a spectrum of LHON and Leigh-like encephalopathy with distinguishing MRI features.
    Keywords:  LHON; Leigh syndrome; MRI; clinical phenotype; m.3890G>A/MT-ND1 mtDNA pathogenic variant
  3. Commun Biol. 2021 Aug 19. 4(1): 989
      Mouse models of genetic mitochondrial disorders are generally used to understand specific molecular defects and their biochemical consequences, but rarely to map compensatory changes allowing survival. Here we took advantage of the extraordinary mitochondrial resilience of hepatic Lrpprc knockout mice to explore this question using native proteomics profiling and lipidomics. In these mice, low levels of the mtRNA binding protein LRPPRC induce a global mitochondrial translation defect and a severe reduction (>80%) in the assembly and activity of the electron transport chain (ETC) complex IV (CIV). Yet, animals show no signs of overt liver failure and capacity of the ETC is preserved. Beyond stimulation of mitochondrial biogenesis, results show that the abundance of mitoribosomes per unit of mitochondria is increased and proteostatic mechanisms are induced in presence of low LRPPRC levels to preserve a balance in the availability of mitochondrial- vs nuclear-encoded ETC subunits. At the level of individual organelles, a stabilization of residual CIV in supercomplexes (SCs) is observed, pointing to a role of these supramolecular arrangements in preserving ETC function. While the SC assembly factor COX7A2L could not contribute to the stabilization of CIV, important changes in membrane glycerophospholipid (GPL), most notably an increase in SC-stabilizing cardiolipins species (CLs), were observed along with an increased abundance of other supramolecular assemblies known to be stabilized by, and/or participate in CL metabolism. Together these data reveal a complex in vivo network of molecular adjustments involved in preserving mitochondrial integrity in energy consuming organs facing OXPHOS defects, which could be therapeutically exploited.
  4. Commun Biol. 2021 Aug 16. 4(1): 974
      Human ATP-dependent Lon protease (LONP1) forms homohexameric, ring-shaped complexes. Depletion of LONP1 causes aggregation of a broad range of proteins in the mitochondrial matrix and decreases the levels of their soluble forms. The ATP hydrolysis activity, but not protease activity, of LONP1 is critical for its chaperone-like anti-aggregation activity. LONP1 forms a complex with the import machinery and an incoming protein, and protein aggregation is linked with matrix protein import. LONP1 also contributes to the degradation of imported, aberrant, unprocessed proteins using its protease activity. Taken together, our results show that LONP1 functions as a gatekeeper for specific proteins imported into the mitochondrial matrix.