bims-cytox1 2023-12-31 papers

Proc Natl Acad Sci U S A. 2024 Jan 02. 121(1): e2310288120

Cytochrome c oxidase deficiency detection in human fibroblasts using scanning electrochemical microscopy.

Shubhneet Thind, Dhésmon Lima, Evan Booy, Dao Trinh, Sean A McKenna, Sabine Kuss.

Cytochrome c oxidase deficiency (COXD) is an inherited disorder characterized by the absence or mutation in the genes encoding for the cytochrome c oxidase protein (COX). COX deficiency results in severe muscle weakness, heart, liver, and kidney disorders, as well as brain damage in infants and adolescents, leading to death in many cases. With no cure for this disorder, finding an efficient, inexpensive, and early means of diagnosis is essential to minimize symptoms and long-term disabilities. Furthermore, muscle biopsy, the traditional detection method, is invasive, expensive, and time-consuming. This study demonstrates the applicability of scanning electrochemical microscopy to quantify COX activity in living human fibroblast cells. Taking advantage of the interaction between the redox mediator N, N, N', N'-tetramethyl-para-phenylene-diamine, and COX, the enzymatic activity was successfully quantified by monitoring current changes using a platinum microelectrode and determining the apparent heterogeneous rate constant k0 using numerical modeling. This study provides a foundation for developing a diagnostic method for detecting COXD in infants, which has the potential to increase treatment effectiveness and improve the quality of life of affected individuals.

Keywords: bioelectrochemistry; biosensing; cytochrome c deficiency; disease detection; scanning electrochemical microscopy

DOI: https://doi.org/10.1073/pnas.2310288120

ESC Heart Fail. 2023 Dec 27.

The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation.

Sebastian Vogt, Rabia Ramzan, Pia Cybulski, Annika Rhiel, Petra Weber, Volker Ruppert, Marc Irqsusi, Susanne Rohrbach, Bernd Niemann, Nikolas Mirow, Ardawan J Rastan.

AIMS: The conditions of hypoxia are suggested to induce permanent atrial fibrillation (AF). The regulation of COX4I2 and COX4I1 depends on oxygen availability in tissues. A role of COX4I2 in the myocardium of AF patients is supposed for pathogenesis of AF and subsequent alterations in the electron transfer chain (ETC) under hypoxia.
METHODS AND RESULTS: In vitro, influence of hypoxia on HeLa 53 cells was studied and elevated parts of COX 4I2 were confirmed. Myocardial biopsies were taken ex vivo from the patients' Right Atria with SR (n = 31) and AF (n = 11), respectively. RT- PCR for mRNA expresson, mitochondrial respiration by polarography and the protein content of cytochrome c oxidase (CytOx) subunit 4I1 and CytOx subunit 4I2 by ELISA were studied. Clinical data were correlated to the findings of gene expressions in parallel. Patients with permanent AF had a change in isoform 4I2/4I1 expression along with a decrease of isoform COX 4I1 expression. The 4I2/4I1 ratio of mRNA expression was increased from 0.630 to 1.058 in comparison. However, the protein content of CytOx subunit 4 was much lower in the AF group, whereas the respiration/units enzyme activity in both groups remained the same.
CONCLUSIONS: This study describes a possible molecular correlate for the development of AF. Due to the known functional significance of COX 4I2, mitochondrial dysfunction can be assumed as a part of the pathogenesis of AF.

Keywords: Cytochrome c oxidase subunit 4; Isoform 4I1 and isoform 4I2; Mitochondrial respiration; Permanent atrial fibrillation

DOI: https://doi.org/10.1002/ehf2.14607

J Nutr. 2023 Dec 21. pii: S0022-3166(23)72821-6. [Epub ahead of print]

COX19 is a new target of MACC1 and promotes colorectal cancer progression by regulating copper transport in mitochondria.

Sheng Gao, Xiaodong Zhang, Jian Wang, Wenqi Bai, Bo Jiang.

BACKGROUND: Recent studies have demonstrated that Cu plays an important role in the progression of tumor diseases. Metastasis associated with colon cancer protein 1 (MACC1) promotes the transcription and expression of various tumor-related genes. Cytochrome c oxidase (COX) 19, present in the cytoplasm and intermembrane space of mitochondria, may transport Cu within the mitochondria. However, the mechanism through which MACC1 regulates the Cu homeostasis mediated by COX19 remains unclear.
OBJECTIVES: The aim of this study was to elucidate the mechanism through which MACC1 initiates the transcription and expression of COX19, and promotes malignant behavior in tumor cells.
METHODS: Immunohistochemistry, western blotting, and real-time PCR analyses were conducted to analyze the expression of MACC1 and COX19 proteins and genes in tumor and normal tissues. RNA-CHIP was used to detect the transcriptional initiation of COX19 by MACC1. The effects of MACC1 and COX19 on mitochondrial activity were determined using an ATP assay kit and Cytochrome c Oxidase Assay Kit. A CCK-8 kit was used to detect the effect of high-dose Cu or overexpression of MACC1 and COX19 on tumor cell proliferation. A xenograft mouse model was used to analyze the effect of COX19 overexpression on the malignant behavior of the tumors.
RESULTS: Cu enhanced the proliferation, invasion, and migration and inhibited apoptosis of SW480 cells. MACC1 was highly expressed in colorectal cancer tissues and activated the expression of COX19 by binding to its promoter region of COX19. The overexpression of COX19 increased mitochondrial Cu content and enhanced the activity of mitochondrial COX and ATP content, and inhibited apoptosis, promoted tumor growth of mice.
CONCLUSIONS: Our results indicate that COX19 functions as a target gene of MACC1 and regulates mitochondrial activity and promotes the progression of colorectal cancer. MACC1/COX19 may provide a novel therapeutic target for colorectal cancer.

Keywords: COX19; Colorectal cancer; Copper metabolic; MACC1

DOI: https://doi.org/10.1016/j.tjnut.2023.12.032