bims-cytox1 2026-06-07 papers

bims-cytox1

Biomed News

on Cytochrome oxidase subunit 1

Issue of 2026–06–07
six papers selected by
Gavin McStay, Liverpool John Moores University

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.
Consequences of defective mitochondrial protein import: From targeting signals to pathology.
Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report.
Redox signals and oxidative stress in the control of mitochondrial protein import.
Correction to: Heart is the most susceptible organ in an isogenic background to loss of function mutations in the mitochondrial metallochaperone SCO1.
Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing mitochondrial DNA damage responses.

Nat Commun. 2026 May 30.

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.

Micol Falabella, Sandra Lopez Calcerrada, Jana Aref, Jiaze Gao, William L Macken, Chiara Pizzamiglio, Renata Kabiljo, Anna Lucia Francavilla, Pauline Gaignard, Antoine Pouzet, Jonathan Levy, Giulia Barcia, Jamie K Leighton, Efstathia Chronopoulou, Germaine Pierre, Riza Köksal Özgül, Ali Dursun, Rebecca Halligan, Helen Mundy, Javeria Raza Alvi, Tipu Sultan, William James Craigen, Lisa Emrick, Jill A Rosenfeld, Gehad Elmakkawy, JiHye Kim, Joseph J Gleeson, Aboulfazl Rad, Gabriela Oprea, Maqbool Hussain, Khalil Ur Rehman, Sadia Riaz, Robert W Taylor, Vincent Procaccio, Maha S Zaki, Erika Fernandez-Vizarra, Ciro Leonardo Pierri, Michael G Hanna, Henry Houlden, Reza Maroofian, Cristina Ugalde, Jan-Willem Taanman, Robert D S Pitceathly.

Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential.

DOI: https://doi.org/10.1038/s41467-026-73455-9
Biochim Biophys Acta Biomembr. 2026 Jun 03. pii: S0005-2736(26)00049-0. [Epub ahead of print] 184546

Consequences of defective mitochondrial protein import: From targeting signals to pathology.

Maya Cielo Cornejo, Sandy Che-Eun S Lee, Shaya Smith, Carla M Koehler.

  Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.

Keywords:  Mitochondria; Mitochondrial disorders; Mitochondrial protein import; Mitochondrial protein processing; Mitochondrial targeting sequence; Proteostasis; TIM23 complex; TOM complex

DOI:  https://doi.org/10.1016/j.bbamem.2026.184546
Mol Syndromol. 2026 Jun;17(3): 288-295

Two Siblings with LRPPRC Mutation: Mitochondrial Complex IV Deficiency: Case Report.

Merve Setenay Akyüzlüer Güneş, Duygu Duman, Emine Kübra Şen, Miraç Yıldırım, Elif Özsu, Ömer Erdeve, Seda Kaynak Şahap, Fatma Tuba Eminoğlu, Engin Köse.

   Introduction: Mitochondrial diseases caused by mutations in the LRPPRC gene are rare and lead to multisystemic dysfunction. We report two siblings from consanguineous Iraqi parents, both harboring a rare homozygous deletion in LRPPRC (c.2726_2728del; p.Lys909del), previously reported in one other patient. These cases contribute to the expanding phenotypic and geographic spectrum of LRPPRC-related mitochondrial disease.
Case Presentation: The younger sibling, a 9-year-old girl, presented with severe growth retardation, global developmental delay, hypotonia, spastic ataxic gait, and lactic acidosis. Magnetic resonance imaging showed symmetrical hyperintensities in the mesencephalon and thalami, cerebellar atrophy, and an inverted lactate peak on spectroscopy. Hypertrophic cardiomyopathy was also detected. The older sibling, aged 13, exhibited milder manifestations, including axial hypotonia, tremor, ataxia, and persistent hyperlactatemia. Both siblings had elevated lactate levels but otherwise normal metabolic panels. Whole exome sequencing revealed a homozygous mutation in the LRPPRC gene (c.2726_2728del; p.Lys909del) in both patients.
Conclusions: These cases highlight the clinical variability of LRPPRC-related disorders. Our report underscores the importance of considering LRPPRC mutations in the differential diagnosis of early-onset neurodevelopmental delay and multisystemic dysfunction with lactic acidosis, especially in populations with high rates of consanguinity. Early genetic diagnosis via whole exome sequencing is essential for accurate diagnosis, genetic counseling, and family planning.

Keywords:  Ataxia; French-Canadian Leigh syndrome; LRPPRC; Mitochondrial complex IV deficiency

DOI:  https://doi.org/10.1159/000548731
Protein Sci. 2026 Jul;35(7): e70665

Redox signals and oxidative stress in the control of mitochondrial protein import.

Lidwina Hasberg, Viktoria Katharina Lauterbach, Torsten Ochsenreiter, Jan Riemer.

  Mitochondrial protein import is essential for organelle biogenesis and cellular homeostasis. It operates in an environment that is intrinsically shaped by redox chemistry. Mitochondria are major sources of reactive oxygen species (ROS), which arise as by-products of oxidative phosphorylation. Cells therefore maintain sophisticated ROS-handling systems, including compartmentalized antioxidant networks, to balance redox signaling with protection from oxidative stress. Increasing evidence indicates that these redox conditions directly influence mitochondrial protein import at multiple levels. In this review, we provide an overview of ROS production, ROS signaling, and oxidative stress in relation to mitochondrial protein import. We outline the major mitochondrial protein import pathways, and discuss how their activity is modulated by redox-dependent mechanisms. A particular focus is placed on the mitochondrial disulfide relay system of the intermembrane space, which directly couples protein import to redox chemistry through oxidative folding, and how it is influenced by the local redox environment. Collectively, we propose that mitochondrial protein import is partially governed by redox-dependent mechanisms, enabling integration of metabolic state, stress responses, and signaling pathways.

Keywords:  disulfide relay; mitochondrial protein import; oxidative stress; reactive oxygen species (ROS); redox signaling

DOI:  https://doi.org/10.1002/pro.70665
Hum Mol Genet. 2026 Jun 01. pii: ddag048. [Epub ahead of print]35(10):

Correction to: Heart is the most susceptible organ in an isogenic background to loss of function mutations in the mitochondrial metallochaperone SCO1.

DOI: https://doi.org/10.1093/hmg/ddag048
Sci Rep. 2026 Jun 04.

Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing mitochondrial DNA damage responses.

Yuki Takakura, Seika Kawamura, Yui Hashiguchi, Manami Yamanaka, Yasuyuki Kurihara, Taishin Akiyama, Hiroyuki Takano, Noritaka Yamaguchi.

DNA-damaging anticancer agents selectively kill highly proliferative cancer cells by inducing DNA damage, such as DNA double- or single-strand breaks, and by inhibiting DNA replication and transcription. These agents have been used for cancer chemotherapy for a long time; however, acquired resistance remains a serious problem that limits their effectiveness. Although mitochondria have their own DNA, which is distinct from nuclear DNA, the involvement of mitochondria and mitochondrial DNA (mtDNA) in resistance to DNA-damaging anticancer agents remains largely unknown. In this study, we found that the mitochondrial small protein cytochrome c oxidase-associated subunit FA4-like 3 (COXFA4L3), formerly known as C15ORF48, confers resistance to DNA-damaging anticancer agents. Mechanistically, DNA-damaging anticancer agents damage mtDNA and induce the cytosolic release of TFAM-unbound mtDNA via the mitochondrial permeability transition pore (mPTP), thereby promoting cell death via activation of the innate immune signalling cGAS-STING pathway. COXFA4L3 inhibits the cytosolic release of mtDNA by repressing mtDNA damage and mPTP opening. These results suggest that mitochondria affect sensitivity to DNA-damaging anticancer agents through COXFA4L3-mediated repression of mtDNA damage responses.

DOI: https://doi.org/10.1038/s41598-026-54548-3