bims-cytox1 2025-10-05 papers

Mitochondrion. 2025 Sep 28. pii: S1567-7249(25)00079-0. [Epub ahead of print] 102082

COXFA4L3 enhances mitochondrial complex IV function to boost ATP synthesis and drive sperm motility.

Reiji Tokito, Kosei Oishi, Tomoya Sugiyama, Yusuke Fujisawa, Fujino Kuba, Kaito Yoshida, Kaoru Yoshida, Manabu Yoshida, Yoichiro Tanaka, Taku Amo, Noritaka Yamaguchi, Taishin Akiyama, Yuji Imai, Kazuto Yoshimi, Tsuyoshi Koide, Yasuyuki Kurihara.

COXFA4L3 is a testis-specific cytochrome c oxidase subunit that enhances mitochondrial complex IV activity during spermatogenesis. From the analysis of Coxfa4l3 knockout mice, the isoform switch from COXFA4 to COXFA4L3 may increase the potential COX activity, although this activity does not appear in the testis. This latent enhancement becomes evident in sperm, where COXFA4L3 promotes higher respiratory capacity, increasing sperm motility and ATP production. These findings indicate that COXFA4L3 is a key regulator of mitochondrial energy metabolism and may provide insights into the mechanisms underlying male infertility.

Keywords: Electron transport chain; Mitochondria; Spermatogenesis

DOI: https://doi.org/10.1016/j.mito.2025.102082

J Hum Genet. 2025 Oct 03.

A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.

Qianyun Cai, Haijiao Wang, Rong Luo, Xiao Qian, Zhongjie Zhou.

Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as COX6A1, are associated with neuromuscular disorders. While recessive COX6A1 variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases. This variant is 41 amino acids longer than the wild-type protein. Functional assays demonstrated significantly reduced mutant protein levels (p < 0.01), supporting the pathogenicity of this mutation. The patient experienced rapid decompensation and died following febrile illness at the age of 3.5 years. This study revealed a novel pathogenic COX6A1 variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease. We report the first COX6A1 stop-loss variant, and our findings expand the phenotypic and genetic spectrum of COX6A1-related disorders.

DOI: https://doi.org/10.1038/s10038-025-01411-4

Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00222-1. [Epub ahead of print]

Interconnectivity of mitochondrial protein biogenesis and quality control.

Abi S Ghifari, Carmela Vazquez-Calvo, Andreas Carlström, Martin Ott.

Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.

Keywords: mitochondria; proteases; protein import; proteolysis; proteostasis; translation

DOI: https://doi.org/10.1016/j.tibs.2025.09.004

Nat Commun. 2025 Sep 30. 16(1): 8680

Chlorella-derived natural photosynthetic system for in situ energy metabolism enhancement in cardiomyocytes.

Yuan Cheng, Lijun Lv, Zhiqiu Cao, Xiaoqing Huang, Yuqiong Wang, Yue Tang, Wen Gao, Bo Tang.

Myocardial ischemia (MI), caused by insufficient blood supply, is a pathological condition where cardiomyocytes lack oxygen and energy supply. Herein, we developed a natural photosynthetic system (HCU) consisting of chlorella pyrenoidosa (C. pyre), hyaluronic acid methacryloyl (HAMA) and degradable upconversion nanoparticles (UCNPs, NaCeF4:Yb,Tm,Zr). Upon near-infrared irradiation, HCU was photo-crosslinked in situ, thereby facilitating C. pyre photosynthetic oxygen generation within the myocardium. Concurrently, cytochrome c oxidase (CCO) in mitochondria was activated to enhance electron transport along the respiratory chain, synergistically boosting cardiac energy metabolism. Consequently, the ATP levels were elevated, and the hypoxic microenvironment was mitigated. In MI mouse models, echocardiography readings returned to normal levels, and the infarct size was significantly reduced following a 7-day treatment with HCU. Based on the photosynthetic system, this study proposes an in situ oxygen and energy metabolic regulation strategy for MI, holding certain inspiration for other ischemia diseases.

DOI: https://doi.org/10.1038/s41467-025-63749-9

Stem Cell Res Ther. 2025 Sep 29. 16(1): 526

MSCs-derived HGF alleviates senescence after AKI by modulating mitoSTAT3-controlled copper flux and respiration.

Kaiting Zhuang, Wenjuan Wang, Cheng Xu, Siyang Wang, Yuhao Chen, Yingjie Zhang, Yanjun Liang, Xumin Zheng, Xiangmei Chen, Zhe Feng, Guangyan Cai.

BACKGROUND: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can reverse senescence after acute kidney injury (AKI) via maintaining mitochondrial homeostasis. Copper accumulation and STAT3 nuclear translocation promote senescence, but their mitochondrial localization in response to MSCs remains unclear.
METHODS: C57 mice with renal unilateral ischemia reperfusion injury (uIRI) were renal capsular transplanted with hUC-MSCs for two weeks to assessed treatment efficacy. Then, RNA sequencing, protein co-immunoprecipitation, molecular docking, and molecular dynamic simulation were used to found the relationship between senescence, mitochondrial translocation of STAT3 (mitoSTAT3), and copper homeostasis. Furthermore, inhibition of cMet/HGFR, mitoSTAT3, or COX17 were used to validated their contact.
RESULTS: HUC-MSCs improved renal function, reduced senescence markers (SA-β-gal, p53, p21, p16), and increased STAT3pSer727 and COX17 levels. RNA sequencing revealed that senescence regulation is associated with copper homeostasis and respiratory chain complex IV. Blocking MSCs-derived HGF via lentivirus decreased STAT3pSer727, COX17, and mt-Co1 (a key subunit of complex IV). Co-immunoprecipitation and molecular docking confirmed tight binding between STAT3pSer727 and COX17. Inhibiting cMet produced similar effects as HGF deficiency, with increasing mitochondrial copper and decreasing mt-Co1. In hypoxic renal tubular epithelial cells (RTECs), blocking HGF or cMet diminished STAT3 mitochondrial translocation, and inhibiting mitoSTAT3 decreased COX17 and mt-Co1. Furthermore, knockdown COX17 aggravated loss of complex IV activity, copper accumulation and RTECs senescence.
CONCLUSIONS: HUC-MSCs-derived HGF promotes STAT3 mitochondrial translocation via cMet, enhancing mitochondrial respiration and copper excretion through COX17, thereby reducing renal senescence after AKI.

Keywords: Acute kidney injury (AKI); Cellular senescence; Copper flux; Hepatocyte growth factor (HGF); Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs); Mitochondrial STAT3 (mitoSTAT3)

DOI: https://doi.org/10.1186/s13287-025-04653-3