bims-cytox1 2020-11-15 papers

Issue of 2020–11–15
four papers selected by
Gavin McStay, Staffordshire University

Hum Mutat. 2020 Nov 10.

A Novel Variant in COX16 Causes Cytochrome c Oxidase Deficiency, Severe Fatal Neonatal Lactic Acidosis, Encephalopathy, Cardiomyopathy and Liver Dysfunction.

Liesbeth T M Wintjes, Maina Kava, Frans A van den Brandt, Mariël A M van den Brand, Oksana Lapina, Yngve T Bliksrud, Mari Ann Kulseth, Silja Svanstrøm Amundsen, Terje R Selberg, Marion Ybema-Antoine, Omar A Z Tutakhel, Lawrence Greed, David R Thorburn, Trine Tangeraas, Shanti Balasubramaniam, Richard J T Rodenburg.

COX16 is involved in the biogenesis of cytochrome-c-oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain (RC). We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p.Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild-type COX16 cDNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease. This article is protected by copyright. All rights reserved.

Keywords: COX16; OXPHOS; assembly factor; cardio-encephalopathy; mitochondrial complex IV deficiency

DOI: https://doi.org/10.1002/humu.24137

Life (Basel). 2020 Nov 11. pii: E277. [Epub ahead of print]10(11):

Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies.

Christina Wasmus, Jan Dudek.

The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.

Keywords: Barth syndrome; Dilated Cardiomyopathy with Ataxia; Sengers syndrome; cardiolipin; cardiomyopathy; mitochondria; respiratory chain

DOI: https://doi.org/10.3390/life10110277

Biochim Biophys Acta Bioenerg. 2020 Nov 07. pii: S0005-2728(20)30185-7. [Epub ahead of print] 148335

CYTOCHROME c OXIDASE DEFICIENCY.

Michele Brischigliaro, Massimo Zeviani.

Cytochrome c oxidase (COX) deficiency is characterized by a high degree of genetic and phenotypic heterogeneity, partly reflecting the extreme structural complexity, multiple post-translational modification, variable, tissue-specific composition, and the high number of and intricate connections among the assembly factors of this enzyme. In fact, decreased COX specific activity can manifest with different degrees of severity, affect the whole organism or specific tissues, and develop a wide spectrum of disease natural history, including disease onsets ranging from birth to late adulthood. More than 30 genes have been linked to COX deficiency, but the list is still incomplete and in fact constantly updated. We here discuss the current knowledge about COX in health and disease, focusing on genetic aetiology and link to clinical manifestations. In addition, information concerning either fundamental biological features of the enzymes or biochemical signatures of its defects have been provided by experimental in vivo models, including yeast, fly, mouse and fish, which expanded our knowledge on the functional features and the phenotypical consequences of different forms of COX deficiency.

Keywords: Cytochrome c oxidase; Disease models; Genetics; Mitochondrial diseases; OXPHOS

DOI: https://doi.org/10.1016/j.bbabio.2020.148335

Nucleic Acids Res. 2020 Nov 11. pii: gkaa1011. [Epub ahead of print]

MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.

The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical 'MitoPathways' spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.

DOI: https://doi.org/10.1093/nar/gkaa1011