bims-cytox1 2026-05-17 papers

Mitochondrion. 2026 May 14. pii: S1567-7249(26)00054-1. [Epub ahead of print] 102164

A century of studies on mitochondrial cytochrome c oxidase.

Ulrik Pedroza-Dávila, Yolanda Camacho-Villasana, Diego González-Halphen, Xochitl Perez-Martinez.

Cytochrome c oxidase (CcO, complex IV) is the last component of the respiratory chain, catalyzing the reduction of oxygen to water and the translocation of protons to the inner membrane space. In 1925, David Keilin published his work on the rediscovery of cytochromes, including types a and a3. The same year, Otto Warburg published part of his work on the "respiratory ferment". Both articles are fundamental to bioenergetics and the mitochondrial field. Since its discovery, CcO has been the subject of study in hundreds of laboratories across the world, but there are still many interrogates to be answered. To commemorate the 100th anniversary of the publication of these two seminal works, this review examines various aspects of the history of CcO (complex IV) and the challenges yet to be resolved of this enzyme.

Keywords: Complex IV; Cytochromec oxidase; Cytochromes; History

DOI: https://doi.org/10.1016/j.mito.2026.102164

EXO. 2026 ;pii: 202605. [Epub ahead of print]1(1):

Heme, copper, and a new way to kill cancer cells.

Xi Zhao, Li Zhuang, Boyi Gan.

Heme homeostasis influences mitochondrial metabolism and leukemia stem cell biology in acute myeloid leukemia. Lewis et al. uncover a surprising metabolic vulnerability in acute myeloid leukemia: suppression of heme biosynthesis primes leukemic cells for cuproptosis, a form of copper-dependent cell death. By linking heme depletion to mitochondrial cytochrome c oxidase (Complex IV) dysfunction, copper accumulation, and cuproptosis, the study integrates transcriptional regulation, mitochondrial metabolism, and metal homeostasis into a unified framework for selective cancer cell killing.

Keywords: BTB and CNC homology 1; Heme; acute myeloid leukemia; copper; cuproptosis

DOI: https://doi.org/10.70401/EXO.2026.0004

Biomed Opt Express. 2026 Apr 01. 17(4): 1649-1672

MW-FlexNIRS: wearable, low-cost, LED-based, multi-wavelength NIRS oximeter for cytochrome c oxidase recovery in neonates.

Nikola Otic, Mitchell B Robinson, Kuan-Cheng Wu, John Sunwoo, Julia Davis, Olivia Kierul, Emily Herzberg, Maria Angela Franceschini, Marco Renna.

We present MW-FlexNIRS, a wearable, low-cost, LED-based, multi-wavelength near-infrared spectroscopy (NIRS) system designed for continuous monitoring of cerebral oxygenation and metabolic dynamics in neonates. The device extends the original FlexNIRS platform by integrating custom eight-wavelength LED sources, a new analog front-end, and Bluetooth low energy 5 communication onto a single flexible printed circuit board encapsulated in medical-grade silicone. To support quantitative analysis with broadband LED sources, we introduce a wavelength-weighted fitting (WWF) algorithm that explicitly accounts for LED emission spectra, photodiode responsivity, and tissue optical properties. System performance was characterized through spectral calibration, stability testing, and noise equivalent power measurements, yielding an average NEP of 123 ± 25 fW/√Hz. Validation experiments using solid silicone phantoms demonstrated accurate recovery of effective attenuation coefficients with a mean error of 2.1% using a calibrated multi-distance approach. Liquid phantom studies incorporating blood, Intralipid, and yeast were used to evaluate recovery of hemoglobin and to investigate cytochrome c oxidase (CCO) related spectral sensitivity, parameter coupling, and model limitations. Finally, a pilot measurement in a term infant with transient respiratory distress demonstrates the preliminary feasibility of stable, continuous cerebral oxygenation monitoring in the neonatal intensive care unit. Together, these results support MW-FlexNIRS as a promising platform for multi-wavelength wearable NIRS in neonates and highlight both the potential and current challenges of oxCCO quantification.

DOI: https://doi.org/10.1364/BOE.590418

Cells. 2026 Apr 29. pii: 811. [Epub ahead of print]15(9):

Inhibitory Effect of ATP on Cytochrome c Oxidase Depends on Electron Entry Pathways by TCA Cycle Metabolites.

Madeline Günther, Valeria Pakic, Petra Weber, Anke Veit, Carsten Culmsee, Ardawan J Rastan, Annegret P Busch, Sebastian Vogt.

The ATP-dependent inhibition of cytochrome c oxidase (CytOx, complex IV of the electron transport chain) is the second mechanism of respiratory control adjusting mitochondrial respiration in order to prevent excessive electron flow and reactive oxygen species (ROS) production. Here, we investigate how tricarboxylic acid (TCA) cycle metabolites and the subsequent complex I or complex II activities influence this regulatory mechanism. Therefore, CytOx activity was assessed by the oxygen consumption rate after cytochrome c (Cyt c) titration to stimulate complex IV activity in isolated rat heart mitochondria (RHM) and permeabilized AC16 cells. Mitochondrial membrane potential (Δψm) and ROS formation were analysed by flow cytometry. Our results show that TCA cycle intermediates differed in their impact on CytOx activity and subsequent ROS formation. NADH-linked substrates such as α-ketoglutarate, glutamate and malate increased respiratory capacity, but preserved ATP-dependent control of CytOx, indicating that elevated electron supply alone does not necessarily abolish ATP sensitivity. In contrast, succinate, which feeds electrons directly into complex II, strongly increased respiration causing the loss of ATP-dependent respiratory control in both model systems. Despite this strong respiratory effect, succinate induced only modest changes in mitochondrial membrane potential in isolated mitochondria, whereas permeabilized cardiomyocytes exhibited reduced polarization accompanied by increased superoxide formation. Together, these findings demonstrate that the effectiveness of ATP-dependent CytOx inhibition is influenced by TCA cycle activity and depends on the site of electron entry into the respiratory chain. Thus, substrate-dependent modulation of respiratory control links metabolite availability to mitochondrial redox regulation in cardiac cells.

Keywords: ATP-dependent inhibition; TCA cycle metabolites; cardiac mitochondria; complex I and II; cytochrome c oxidase; mitochondrial ROS; respiratory control

DOI: https://doi.org/10.3390/cells15090811

Mol Microbiol. 2026 May 11.

Mitochondrial Localization and Abundance of Leishmania Cytochrome c Oxidase Subunit IV Is Maintained Following Loss of Mitochondrial Membrane Potential Associated With Mammalian Temperature.

Isabel Stephany-Brassesco, Edward J Wojcik, Justin C Smith, Ben L Kelly.

In eukaryotes, exposure to elevated temperature can disrupt cellular activities, including mitochondrial membrane potential (ΔΨm). Among multiple impacts, loss of ΔΨm typically results in mislocalization of nuclear-encoded mitochondria-destined proteins followed by their proteostatic degradation. As part of their natural transmission cycle, Leishmania encounter an abrupt temperature increase when inoculated into mammalian hosts via the bite of phlebotomine sandflies. How Leishmania maintain mitochondrial protein import in the face of this heat stress remains unknown. We therefore examined the relationship between ΔΨm, abundance of L. major cytochrome c oxidase complex subunit IV (LmCOX4) and its cellular localization functions at insect and mammalian temperatures. Intriguingly, LmCOX4 contains both a mitochondrial targeting sequence (MTS LmCOX4) and a PTS-1 glycosomal targeting motif. LmCOX4 is transiently down-modulated following exposure to mammalian temperature, suggesting that heat-induced loss of ΔΨm could lead to LmCOX4 mislocalization and degradation. We find, however, that while transient down-modulation of LmCOX4 promotes viability at mammalian temperature, the associated loss of ΔΨm impacts neither MTSLmCOX4-mediated localization nor LmCOX4 abundance. Unexpectedly, the canonical positive charges of MTSLmCOX4 are dispensable for mitochondrial localization. Further, LmCOX4's glycosomal targeting sequence has no apparent role in cellular localization at insect or mammalian temperatures.

Keywords: Leishmania ; cytochrome c oxidase; import; life cycle; mitochondrion; protein abundance

DOI: https://doi.org/10.1111/mmi.70077

Mol Reprod Dev. 2026 05;93(5): e70110

High-Resolution Imaging Reveals Mitochondrial Protein Imbalance in Sperm of Oligoasthenospermic Men.

Pauline Teixeira, Magalie Boguenet, Florence Pascaretti-Grizon, Florence Manero, Solenn Plouzennec, Pierre-Emmanuel Bouet, Pascal Reynier, Arnaud Chevrollier, Pascale May-Panloup.

Male infertility accounts for nearly half of global infertility cases and is often linked to poor sperm quality, such as oligospermia, asthenospermia, and teratospermia. Although the exact mechanisms remain unclear, mitochondria, which are critical for ATP production and reactive oxygen species generation during fertilization, are increasingly recognized as key players in male infertility but remain underexplored. ATP synthesis relies on respiratory chain complexes that establish a proton gradient across the inner mitochondrial membrane, powering the F0F1-ATP synthase. Proper stoichiometry of these complexes, encoded by both nuclear and mitochondrial DNA, is essential for efficient energy production. However, no previous studies have directly correlated mitochondrial protein expression with sperm quality. Due to the small size and helical structure of sperm mitochondria, imaging them is challenging, yet crucial for understanding sperm function. This study investigates the role of mitochondrial oxidative phosphorylation proteins in sperm quality using single-cell immunolabeling and high-resolution microscopy. It compares spermatozoa from oligoasthenospermic (OA) patients to normospermic controls. OA sperm show increased levels of mitochondrial genome encoded cytochrome c oxidase subunit 1 and significantly reduced F0F1-ATP synthase subunits. This imbalance may contribute to mitochondrial dysfunction and underscores the need for deeper exploration of the pathophysiological mechanisms involved, which could affect sperm function and fertility. These initial results suggest a potential pathway toward the identification of novel biomarkers of male infertility.

Keywords: OXPHOS; infertility; microscopy; mitochondria; sperm

DOI: https://doi.org/10.1002/mrd.70110