bims-cytox1 2021-10-17 papers

Issue of 2021–10–17
four papers selected by
Gavin McStay, Staffordshire University

Front Cardiovasc Med. 2021 ;8 749756

Role of the Mitochondrial Protein Import Machinery and Protein Processing in Heart Disease.

Mitochondria are essential organelles for cellular energy production, metabolic homeostasis, calcium homeostasis, cell proliferation, and apoptosis. About 99% of mammalian mitochondrial proteins are encoded by the nuclear genome, synthesized as precursors in the cytosol, and imported into mitochondria by mitochondrial protein import machinery. Mitochondrial protein import systems function not only as independent units for protein translocation, but also are deeply integrated into a functional network of mitochondrial bioenergetics, protein quality control, mitochondrial dynamics and morphology, and interaction with other organelles. Mitochondrial protein import deficiency is linked to various diseases, including cardiovascular disease. In this review, we describe an emerging class of protein or genetic variations of components of the mitochondrial import machinery involved in heart disease. The major protein import pathways, including the presequence pathway (TIM23 pathway), the carrier pathway (TIM22 pathway), and the mitochondrial intermembrane space import and assembly machinery, related translocases, proteinases, and chaperones, are discussed here. This review highlights the importance of mitochondrial import machinery in heart disease, which deserves considerable attention, and further studies are urgently needed. Ultimately, this knowledge may be critical for the development of therapeutic strategies in heart disease.

Keywords: CHCHD4 (MIA40); TIM22 complex; TIM23 complex; TOM complex; heart disease; mitochondrial protein import machinery

DOI: https://doi.org/10.3389/fcvm.2021.749756

Orphanet J Rare Dis. 2021 Oct 09. 16(1): 413

Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases.

Anna Ardissone, Claudio Bruno, Daria Diodato, Alice Donati, Daniele Ghezzi, Eleonora Lamantea, Costanza Lamperti, Michelangelo Mancuso, Diego Martinelli, Guido Primiano, Elena Procopio, Anna Rubegni, Filippo Santorelli, Maria Cristina Schiaffino, Serenella Servidei, Flavia Tubili, Enrico Bertini, Isabella Moroni.

BACKGROUND: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database.
RESULTS: Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date.
CONCLUSION: We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.

Keywords: Basal ganglia; Childhood; Leigh syndrome; Mitochondrial disease

DOI: https://doi.org/10.1186/s13023-021-02029-3

Int J Mol Sci. 2021 Sep 26. pii: 10344. [Epub ahead of print]22(19):

Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity.

Ajibola B Bakare, Joseph Dean, Qun Chen, Vedant Thorat, Yimin Huang, Thomas LaFramboise, Edward J Lesnefsky, Shilpa Iyer.

Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood. To better understand this relationship, we computed a glycolytic bioenergetics health index (BHI) for measuring mitochondrial dysfunction in LS patient fibroblast cells harboring varying percentages of pathogenic mutant mtDNA (T8993G, T9185C) exhibiting deficiency in complex V or complex I (T10158C, T12706C). A high percentage (>90%) of pathogenic mtDNA in cells affecting complex V and a low percentage (<39%) of pathogenic mtDNA in cells affecting complex I was quantified. Levels of defective enzyme activities of the electron transport chain correlated with the percentage of pathogenic mtDNA. Subsequent bioenergetics assays showed cell lines relied on both OXPHOS and glycolysis for meeting energy requirements. Results suggest that whereas the precise mechanism of LS has not been elucidated, a multi-pronged approach taking into consideration the specific pathogenic mtDNA variant, glycolytic BHI, and the composite BHI (average ratio of oxphos to glycolysis) can aid in better understanding the factors influencing disease severity in LS.

Keywords: bioenergetics health index; glycolysis; leigh syndrome; mitochondrial disorders; mitochondrial respiration

DOI: https://doi.org/10.3390/ijms221910344

Nucleic Acids Res. 2021 Oct 11. pii: gkab789. [Epub ahead of print]

Translational activators and mitoribosomal isoforms cooperate to mediate mRNA-specific translation in Schizosaccharomyces pombe mitochondria.

Christopher J Herbert, Sylvie Labarre-Mariotte, David Cornu, Cyrielle Sophie, Cristina Panozzo, Thomas Michel, Geneviève Dujardin, Nathalie Bonnefoy.

Mitochondrial mRNAs encode key subunits of the oxidative phosphorylation complexes that produce energy for the cell. In Saccharomyces cerevisiae, mitochondrial translation is under the control of translational activators, specific to each mRNA. In Schizosaccharomyces pombe, which more closely resembles the human system by its mitochondrial DNA structure and physiology, most translational activators appear to be either lacking, or recruited for post-translational functions. By combining bioinformatics, genetic and biochemical approaches we identified two interacting factors, Cbp7 and Cbp8, controlling Cytb production in S. pombe. We show that their absence affects cytb mRNA stability and impairs the detection of the Cytb protein. We further identified two classes of Cbp7/Cbp8 partners and showed that they modulated Cytb or Cox1 synthesis. First, two isoforms of bS1m, a protein of the small mitoribosomal subunit, that appear mutually exclusive and confer translational specificity. Second, a complex of four proteins dedicated to Cox1 synthesis, which includes an RNA helicase that interacts with the mitochondrial ribosome. Our results suggest that S. pombe contains, in addition to complexes of translational activators, a heterogeneous population of mitochondrial ribosomes that could specifically modulate translation depending on the mRNA translated, in order to optimally balance the production of different respiratory complex subunits.

DOI: https://doi.org/10.1093/nar/gkab789