bims-cytox1 2025-11-23 papers

Mitochondrion. 2025 Nov 16. pii: S1567-7249(25)00096-0. [Epub ahead of print] 102099

The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.

Jakob D Busch, Thomas Schöndorf, Dusanka Milenkovic, Xinping Li, Rolf Wibom, Joana F Silva-Rodrigues, Roberta Filograna, Camilla Koolmeister, Nils-Göran Larsson, Diana Rubalcava-Gracia.

The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 in vivo, we generated Tmem177 knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, Tmem177 and Surf1 double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 in vivo. Our findings refine the current model of complex IV assembly in mammals.

Keywords: Cytochrome c oxidase; Mitochondria; Mitoribosomes; OXPHOS; mtDNA

DOI: https://doi.org/10.1016/j.mito.2025.102099

bioRxiv. 2025 Oct 02. pii: 2025.10.01.679889. [Epub ahead of print]

Association of cytochrome c oxidase dysfunction with amyloidosis in Alzheimer's disease and patient-derived cerebral organoids.

Tienju Wang, Yanting Chen, Jing Tian, Khloud Emam, Lan Guo, Tao Ma, Heng Du.

Patients with Alzheimer's disease (AD) demonstrate brain mitochondrial dysfunction and energy deficiency that are closely associated with cognitive impairment. Cytochrome c oxidase (CCO), also known as mitochondrial complex IV, is the terminal enzyme in mitochondrial electron transport chain (ETC). Consistent with the pivotal role of CCO in mitochondrial bioenergetics and high demand for energy to sustain neuronal function, CCO dysfunction has been linked to neurological disorders including AD. However, it remains unclear whether mitochondrial CCO dysfunction represents an adaptive response to AD-associated toxic molecules versus a bona fide pathology to promote AD development. In this study, by meta-analysis of publicly available proteomics analysis of post-mortem frontal lobe tissues from four large cohorts of patients with AD we identified loss of key CCO subunits including mitochondrial DNA (mtDNA)-encoded COX1 and COX3 as well as nuclear DNA (nDNA)-encoded COX5A, COX6B1, COX7C, COX8A, and NDUFA4 in patients with AD. Further biochemical analysis using post-mortem frontal lobe tissues showed lowered CCO activity of neuronal mitochondria from patients with AD, suggesting CCO vulnerability and its potential association with amyloidosis in AD. Lastly, in addition to the inverse relationship between neuronal CCO activity and brain amyloidosis in the tested AD cohort, pharmacological inhibition of CCO promoted amyloid production and elevated beta-secretase 1 (BACE1) activity in cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) from one nonAD and one AD subject. The simplest interpretation of the results is that CCO dysfunction in the frontal lobe is a phenotypic mitochondrial change accompanying AD, which may contribute to the development of brain amyloidosis.

DOI: https://doi.org/10.1101/2025.10.01.679889

Res Sq. 2025 Oct 05. pii: rs.3.rs-7760901. [Epub ahead of print]

Absolute quantification of redox state of cytochrome c oxidase and hemoglobin in human tissue using continuous-wave broadband near-infrared spectroscopy.

Fatemeh Tavakoli, Xinlong Wang, Hanli Liu.

Using the diffusion approximation, we developed a continuous-wave (CW) broadband near-infrared spectroscopy (bb-NIRS) system to noninvasively quantify the absolute concentrations of redox state of cytochrome c oxidase [CCO] and other major human tissue chromophores. The algorithm leverages characteristic spectral features obtained from the first and second derivative domains of wavelength-dependent extinction coefficients. The validation of the method was performed through computational simulations to evaluate estimation accuracy, followed by in vivo measurements on the forearms of 20 participants and the foreheads of 18 participants. The recovered values showed strong agreement with established physiological parameters within maximum of 10% deviation, prior literature, and concurrent frequency-domain near-infrared spectroscopy (FD-NIRS) measurements. These findings demonstrate the feasibility of a CW-based approach for accurate and noninvasive absolute quantification of human tissue components.

DOI: https://doi.org/10.21203/rs.3.rs-7760901/v1

Aging Cell. 2025 Nov 18. e70294

Mitochondrial Respiratory Supercomplex Assembly Factor COX7RP Contributes to Lifespan Extension in Mice.

Kazuhiro Ikeda, Sachiko Shiba, Masataka Yokoyama, Masanori Fujimoto, Kuniko Horie, Tomoaki Tanaka, Satoshi Inoue.

COX7RP is a critical factor that assembles mitochondrial respiratory chain complexes into supercomplexes, which is considered to modulate energy production efficiency. Whether COX7RP contributes to metabolic homeostasis and lifespan remains elusive. We here observed that COX7RP-transgenic (COX7RP-Tg) mice exhibit a phenotype characterized by a significant extension of lifespan. In addition, metabolic alterations were observed in COX7RP-Tg mice, including lower blood glucose levels at 120 min during the glucose tolerance test (GTT) without a significant difference in the area under the curve (AUC), as well as reduced serum triglyceride (TG) and total cholesterol (TC) levels. Moreover, COX7RP-Tg mice exhibited elevated ATP and nicotinamide adenine dinucleotide levels, reduced ROS production, and decreased senescence-associated β-galactosidase levels. Single-nucleus RNA-sequencing (snRNA-seq) revealed that senescence-associated secretory phenotype genes were downregulated in old COX7RP-Tg white adipose tissue (WAT) compared with old WT WAT, particularly in adipocytes. This study provides a clue to the role of mitochondrial respiratory supercomplex assembly factor COX7RP in resistance to aging and longevity extension.

Keywords: lifespan; metabolism; mitochondria; supercomplex; white adipose tissue

DOI: https://doi.org/10.1111/acel.70294

bioRxiv. 2025 Sep 30. pii: 2025.09.29.678879. [Epub ahead of print]

Organ-specific rewiring of mitochondrial integrity through COX7A dictates cellular ploidy control.

Archan Chakraborty, Sophia DeLuca, Meera Gangasani, Stephen Rogers, Nenad Bursac, Donald T Fox.

To achieve proper cell and tissue size, cytoplasmic and nuclear growth must be coordinated. Disrupting this coordination causes birth defects and disease. In nature's largest cells, nuclear growth occurs through polyploidization (whole-genome-duplication). How the massive nuclear growth of polyploid cells is coordinated with cytoplasmic growth processes such as mitochondrial biogenesis is relatively unclear. Here, focusing on one of nature's most commonly polyploid organs-the heart-we uncover cross-talk between cytoplasmic mitochondrial biogenesis/integrity and nuclear growth/polyploidy. From a human-to-fly screen, we uncover novel regulators of cardiomyocyte ploidy, including mitochondrial integrity regulators. In comparing these cardiac hits with a parallel screen in another polyploid tissue, the salivary gland, we discovered two opposing roles for Cytochrome-c-oxidase-subunit-7A (COX7A). While salivary gland COX7A preserves mitochondrial integrity to promote polyploidy and optimal organ growth, cardiac COX7A instead suppresses mitochondrial biogenesis to repress polyploidy and prevent hypertrophic organ growth. Among all electron transport chain genes, only COX7A functions as a cardiac growth repressor. Fly hearts with compromised COX7A show abnormally high cardiac output. Human COX7A1, a mitochondrial-localized protein, similarly represses polyploidy of human iPSC-derived cardiomyocytes. In summary, our human-fly-human approach reveals conserved rewiring of mitochondrial integrity in heart tissue that switches COX7A's role from ploidy promotion to repression. Our findings reveal fundamental cross-talk between mitochondrial biogenesis and genome duplication that are critical in growing metazoan tissues.

DOI: https://doi.org/10.1101/2025.09.29.678879