bims-cytox1 2022-02-20 papers

bims-cytox1

Biomed News

on Cytochrome oxidase subunit 1

Issue of 2022–02–20
seven papers selected by
Gavin McStay, Staffordshire University

Mitochondrial Processing Peptidases-Structure, Function and the Role in Human Diseases.
Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype-Different Onset.
Functional Role of Mitochondrial DNA in Cancer Progression.
Emerging Roles of COX7RP and Mitochondrial Oxidative Phosphorylation in Breast Cancer.
High-Repetition-Rate Transient Absorption Spectroscopy of Respiratory Supercomplexes.
LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria.
Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration.

Int J Mol Sci. 2022 Jan 24. pii: 1297. [Epub ahead of print]23(3):

Mitochondrial Processing Peptidases-Structure, Function and the Role in Human Diseases.

Nina Kunová, Henrieta Havalová, Gabriela Ondrovičová, Barbora Stojkovičová, Jacob A Bauer, Vladena Bauerová-Hlinková, Vladimir Pevala, Eva Kutejová.

  Mitochondrial proteins are encoded by both nuclear and mitochondrial DNA. While some of the essential subunits of the oxidative phosphorylation (OXPHOS) complexes responsible for cellular ATP production are synthesized directly in the mitochondria, most mitochondrial proteins are first translated in the cytosol and then imported into the organelle using a sophisticated transport system. These proteins are directed mainly by targeting presequences at their N-termini. These presequences need to be cleaved to allow the proper folding and assembly of the pre-proteins into functional protein complexes. In the mitochondria, the presequences are removed by several processing peptidases, including the mitochondrial processing peptidase (MPP), the inner membrane processing peptidase (IMP), the inter-membrane processing peptidase (MIP), and the mitochondrial rhomboid protease (Pcp1/PARL). Their proper functioning is essential for mitochondrial homeostasis as the disruption of any of them is lethal in yeast and severely impacts the lifespan and survival in humans. In this review, we focus on characterizing the structure, function, and substrate specificities of mitochondrial processing peptidases, as well as the connection of their malfunctions to severe human diseases.

Keywords:  IMP; MIP; MPP; mitochondrial disease; mitochondrial processing peptidases; mitochondrial rhomboid protease

DOI:  https://doi.org/10.3390/ijms23031297
Cells. 2022 Jan 30. pii: 489. [Epub ahead of print]11(3):

Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype-Different Onset.

Sara Capiau, Joél Smet, Boel De Paepe, Yilmaz Yildiz, Mutluay Arslan, Olivier Stevens, Maxime Verschoore, Hedwig Stepman, Sara Seneca, Arnaud Vanlander.

  Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C variant in MT-ATP6. Patient 1 presented as a toddler with severe motor and speech delay and spastic ataxia without extra-neurologic involvement. Patient 2 presented in adolescence with ataxia and ophthalmoplegia without cognitive or motor impairment. Respiratory chain complex activities were normal in cultured skin fibroblasts from both patients when calculated as ratios over citrate synthase activity. Native gels found presence of subcomplexes of complex V in fibroblast and/or skeletal muscle. Bioenergetic measurements in fibroblasts from both patients detected reduced spare respiratory capacities and altered extracellular acidification rates, revealing a switch from mitochondrial respiration to glycolysis to uphold ATP production. Thus, in contrast to the differing disease presentation, biochemical evidence of mitochondrial deficiency turned out quite similar. We conclude that biochemical analysis remains a valuable tool to confirm the genetic diagnosis of mitochondrial disease, especially in patients with new gene variants or atypical clinical presentation.

Keywords:  ATP-synthase; MT-ATP6; NC_012920.1(MT-ATP6):m.9035T>C; complex V deficiency; genotype-phenotype correlation; mitochondrial disorder; p.L170P

DOI:  https://doi.org/10.3390/cells11030489
Int J Mol Sci. 2022 Jan 31. pii: 1659. [Epub ahead of print]23(3):

Functional Role of Mitochondrial DNA in Cancer Progression.

Yang-Hsiang Lin, Siew-Na Lim, Cheng-Yi Chen, Hsiang-Cheng Chi, Chau-Ting Yeh, Wey-Ran Lin.

  Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.

Keywords:  SNP; cancer; mitochondria; mutation; ncRNA; prognostic marker

DOI:  https://doi.org/10.3390/ijms23031659
Front Cell Dev Biol. 2022 ;10 717881

Emerging Roles of COX7RP and Mitochondrial Oxidative Phosphorylation in Breast Cancer.

Shuhei Kamada, Toshihiko Takeiwa, Kazuhiro Ikeda, Kuniko Horie, Satoshi Inoue.

  Metabolic alterations are critical events in cancers, which often contribute to tumor pathophysiology. While aerobic glycolysis is a known characteristic of cancer-related metabolism, recent studies have shed light on mitochondria-related metabolic pathways in cancer biology, including oxidative phosphorylation (OXPHOS), amino acid and lipid metabolism, nucleic acid metabolism, and redox regulation. Breast cancer is the most common cancer in women; thus, elucidation of breast cancer-related metabolic alteration will help to develop cancer drugs for many patients. We here aim to define the contribution of mitochondrial metabolism to breast cancer biology. The relevance of OXPHOS in breast cancer has been recently defined by the discovery of COX7RP, which promotes mitochondrial respiratory supercomplex assembly and glutamine metabolism: the latter is also shown to promote nucleic acid and fatty acid biosynthesis as well as ROS defense regulation. In this context, the estrogen-related receptor (ERR) family nuclear receptors and collaborating coactivators peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) are essential transcriptional regulators for both energy production and cancer-related metabolism. Summarizing recent findings of mitochondrial metabolism in breast cancer, this review will aim to provide a clue for the development of alternative clinical management by modulating the activities of responsible molecules involved in disease-specific metabolic alterations.

Keywords:  ERR; OxPhos; breast cancer; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fcell.2022.717881
J Phys Chem B. 2022 Feb 15.

High-Repetition-Rate Transient Absorption Spectroscopy of Respiratory Supercomplexes.

Erkang Wang, Kalyn S Specht, Adam J Chicco, Jesse W Wilson.

Hemeproteins are frequent subjects for ultrafast transient absorption spectroscopy (TAS) because of biological importance, strong UV-vis absorption, high photostability, and interesting transient dynamics that depend on redox, conformation, and ligand binding. TAS on hemeproteins is usually performed on isolated, purified proteins, though their response is likely to be different in their native molecular environment, which involves the formation of protein complexes and supercomplexes. Recently, we reported a transient absorption microscopy (TAM) experiment which elicited a transient response from hemeproteins in intact biological tissue using a visible-wavelength pump (530 nm) and probe (490 nm). Here, we find that adaptive noise canceling plus resonant galvanometer scanning enables a high-repetition-rate fiber laser source to make redox-sensitive measurements of cytochrome c (Cyt-c). We investigate the origins of the visible-wavelength response of biological tissue through TAS of intact mitochondrial respiratory supercomplexes, separated via gel electrophoresis. We find that each of these high-molecular-weight gel bands yields a TAS response characteristic of cytochrome hemes, implying that the TAS response of intact cells and tissue originates from not just Cyt-c but a mixture of respiratory cytochromes. We also find differences in excited-state lifetime between wild-type (WT) and a tafazzin-deficient (TAZ) mouse model of mitochondrial disease.

DOI: https://doi.org/10.1021/acs.jpcb.1c08714
Nat Cell Biol. 2022 Feb;24(2): 181-193

LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria.

Qiyuan Yang, Pengpeng Liu, Nadine S Anderson, Tomer Shpilka, YunGuang Du, Nandhitha Uma Naresh, Rui Li, Lihua Julie Zhu, Kevin Luk, Josh Lavelle, Rilee D Zeinert, Peter Chien, Scot A Wolfe, Cole M Haynes.

The accumulation of deleterious mitochondrial DNA (∆mtDNA) causes inherited mitochondrial diseases and ageing-associated decline in mitochondrial functions such as oxidative phosphorylation. Following mitochondrial perturbations, the bZIP protein ATFS-1 induces a transcriptional programme to restore mitochondrial function. Paradoxically, ATFS-1 is also required to maintain ∆mtDNAs in heteroplasmic worms. The mechanism by which ATFS-1 promotes ∆mtDNA accumulation relative to wild-type mtDNAs is unclear. Here we show that ATFS-1 accumulates in dysfunctional mitochondria. ATFS-1 is absent in healthy mitochondria owing to degradation by the mtDNA-bound protease LONP-1, which results in the nearly exclusive association between ATFS-1 and ∆mtDNAs in heteroplasmic worms. Moreover, we demonstrate that mitochondrial ATFS-1 promotes the binding of the mtDNA replicative polymerase (POLG) to ∆mtDNAs. Interestingly, inhibition of the mtDNA-bound protease LONP-1 increased ATFS-1 and POLG binding to wild-type mtDNAs. LONP-1 inhibition in Caenorhabditis elegans and human cybrid cells improved the heteroplasmy ratio and restored oxidative phosphorylation. Our findings suggest that ATFS-1 promotes mtDNA replication in dysfunctional mitochondria by promoting POLG-mtDNA binding, which is antagonized by LONP-1.

DOI: https://doi.org/10.1038/s41556-021-00840-5
Cells. 2022 Feb 07. pii: 578. [Epub ahead of print]11(3):

Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration.

Kumudesh Mishra, Mária Péter, Anna Maria Nardiello, Guy Keller, Victoria Llado, Paula Fernandez-Garcia, Ulf D Kahlert, Dinorah Barasch, Ann Saada, Zsolt Török, Gábor Balogh, Pablo V Escriba, Stefano Piotto, Or Kakhlon.

  The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) has been extensively investigated as a cancer therapy mainly based on its regulation of membrane lipid composition and structure, activating various cell fate pathways. We discovered, additionally, that 2OHOA can uncouple oxidative phosphorylation, but this has never been demonstrated mechanistically. Here, we explored the effect of 2OHOA on mitochondria isolated by ultracentrifugation from U118MG glioblastoma cells. Mitochondria were analyzed by shotgun lipidomics, molecular dynamic simulations, spectrophotometric assays for determining respiratory complex activity, mass spectrometry for assessing beta oxidation and Seahorse technology for bioenergetic profiling. We showed that the main impact of 2OHOA on mitochondrial lipids is their hydroxylation, demonstrated by simulations to decrease co-enzyme Q diffusion in the liquid disordered membranes embedding respiratory complexes. This decreased co-enzyme Q diffusion can explain the inhibition of disjointly measured complexes I-III activity. However, it doesn't explain how 2OHOA increases complex IV and state 3 respiration in intact mitochondria. This increased respiration probably allows mitochondrial oxidative phosphorylation to maintain ATP production against the 2OHOA-mediated inhibition of glycolytic ATP production. This work correlates 2OHOA function with its modulation of mitochondrial lipid composition, reflecting both 2OHOA anticancer activity and adaptation to it by enhancement of state 3 respiration.

Keywords:  2-hydroxyoleic acid; bioenergetics; glycolysis; membrane lipid therapy; mitochondria; molecular dynamics; respiration; shotgun lipidomics

DOI:  https://doi.org/10.3390/cells11030578