bims-mitran Biomed News
on Mitochondrial Translation
Issue of 2022‒10‒02
six papers selected by
Andreas Aufschnaiter
University of Graz

  1. Nat Commun. 2022 Sep 30. 13(1): 5750
      Canonical RNA processing in mammalian mitochondria is defined by tRNAs acting as recognition sites for nucleases to release flanking transcripts. The relevant factors, their structures, and mechanism are well described, but not all mitochondrial transcripts are punctuated by tRNAs, and their mode of processing has remained unsolved. Using Drosophila and mouse models, we demonstrate that non-canonical processing results in the formation of 3' phosphates, and that phosphatase activity by the carbon catabolite repressor 4 domain-containing family member ANGEL2 is required for their hydrolysis. Furthermore, our data suggest that members of the FAST kinase domain-containing protein family are responsible for these 3' phosphates. Our results therefore propose a mechanism for non-canonical RNA processing in metazoan mitochondria, by identifying the role of ANGEL2.
  2. Int J Biochem Cell Biol. 2022 Sep 26. pii: S1357-2725(22)00153-4. [Epub ahead of print] 106308
      Deletion of the Schizosaccharomyces pombe pentatricopeptide repeat gene ppr10 severely impairs mitochondrial translation, resulting in defective oxidative phosphorylation (OXPHOS). ppr10 deletion also induces iron starvation response, resulting in increased reactive oxygen species (ROS) production and reduced viability under fermentative conditions. S. pombe has two principal stress-response pathways, which are mediated by the mitogen-activated protein kinase Sty1 and the basic leucine zipper transcription factor Pap1, respectively. In this study, we examined the roles of Sty1 and Pap1 in the cellular response to the mitochondrial translation defect caused by ppr10 deletion. We found that ppr10 deletion resulted in two waves of stress protein activation. The early response occurred in exponential phase and resulted in the expression of a subset of stress proteins including Gst2 and Obr1. The upregulation of some of these stress proteins in Δppr10 cells in early response is dependent on the basal nuclear levels of Sty1 or Pap1. The late response occurred in early stationary phase and coincided with the stable localization of Sty1 and Pap1 in the nucleus, presumably resulting in persistent activation of a large set of stress proteins. Deletion of sty1 in Δppr10 cells caused severe defects in cell division and growth, and further impaired cell viability. Deletion of the mitochondrial superoxide dismutase gene sod2 whose expression is controlled by Sty1 severely inhibited the growth of Δppr10 cells. Overexpression of sod2 improves the viability of Δppr10 cells. Our results support an important role for Sty1 in counteracting stress induced by ppr10 deletion under fermentative growth conditions. DATA AVAILABILITY: The RNA-Seq data have been deposited in the National Center for Biotechnology Information (NCBI) BioProject database (accession number SRP091623) and Gene Expression Omnibus (GEO) database (accession number GSE90144).
    Keywords:  PPR protein; Pap1; Schizosaccharomyces pombe; Sty1; mitochondria
  3. Front Cell Dev Biol. 2022 ;10 984245
      Mitochondria are the primary sites for cellular energy production and are required for many essential cellular processes. Mitochondrial DNA (mtDNA) is a 16.6 kb circular DNA molecule that encodes only 13 gene products of the approximately 90 different proteins of the respiratory chain complexes and an estimated 1,200 mitochondrial proteins. MtDNA is, however, crucial for organismal development, normal function, and survival. MtDNA maintenance requires mitochondrially targeted nuclear DNA repair enzymes, a mtDNA replisome that is unique to mitochondria, and systems that control mitochondrial morphology and quality control. Here, we provide an overview of the current literature on mtDNA repair and transcription machineries and discuss how dynamic functional interactions between the components of these systems regulate mtDNA maintenance and transcription. A profound understanding of the molecular mechanisms that control mtDNA maintenance and transcription is important as loss of mtDNA integrity is implicated in normal process of aging, inflammation, and the etiology and pathogenesis of a number of diseases.
    Keywords:  DNA repair; base excision repair (BER); base excision repair (BER)glycosylases; mitochdrial damage; mitochondria; transcription
  4. Pharmacol Res. 2022 Sep 26. pii: S1043-6618(22)00412-1. [Epub ahead of print] 106466
      Until recently it was thought that most humans only harbor one type of mitochondrial DNA (mtDNA), however, deep sequencing and single-cell analysis has shown the converse - that mixed populations of mtDNA (heteroplasmy) are the norm. This is important because heteroplasmy levels can change dramatically during transmission in the female germ line, leading to high levels causing severe mitochondrial diseases. There is also emerging evidence that low level mtDNA mutations contribute to common late onset diseases such as neurodegenerative disorders and cardiometabolic diseases because the inherited mutation levels can change within developing organs and non-dividing cells over time. Initial predictions suggested that the segregation of mtDNA heteroplasmy was largely stochastic, with an equal tendency for levels to increase or decrease. However, transgenic animal work and single-cell analysis have shown this not to be the case during germ-line transmission and in somatic tissues during life. Mutation levels in specific mtDNA regions can increase or decrease in different contexts and the underlying molecular mechanisms are starting to be unraveled. In this review we provide a synthesis of recent literature on the mechanisms of selection for and against mtDNA variants. We identify the most pertinent gaps in our understanding and suggest ways these could be addressed using state of the art techniques.
    Keywords:  mitochondria; mitophagy; mtDNA; mutant; selection; selfish
  5. Sci Rep. 2022 Sep 26. 12(1): 16030
      Genetic mutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). Although mitochondrial dysfunction and stress granule have been crucially implicated in FUS proteinopathy, the molecular basis remains unclear. Here, we show that DHX30, a component of mitochondrial RNA granules required for mitochondrial ribosome assembly, interacts with FUS, and plays a crucial role in ALS-FUS. WT FUS did not affect mitochondrial localization of DHX30, but the mutant FUS lowered the signal of mitochondrial DHX30 and promoted the colocalization of cytosolic FUS aggregates and stress granule markers. The immunohistochemistry of the spinal cord from an ALS-FUS patient also confirmed the colocalization, and the immunoelectron microscope demonstrated decreased mitochondrial DHX30 signal in the spinal motor neurons. Subcellular fractionation by the detergent-solubility and density-gradient ultracentrifugation revealed that mutant FUS also promoted cytosolic mislocalization of DHX30 and aggregate formation. Interestingly, the mutant FUS disrupted the DHX30 conformation with aberrant disulfide formation, leading to impaired mitochondrial translation. Moreover, blue-native gel electrophoresis revealed an OXPHOS assembly defect caused by the FUS mutant, which was similar to that caused by DHX30 knockdown. Collectively, our study proposes DHX30 as a pivotal molecule in which disulfide-mediated conformational change mediates mitochondrial dysfunction and cytosolic aggregate formation in ALS-FUS.