MITOCHONDRIAL–REDOX–IMMUNE AXIS: AN INTEGRATIVE MOLECULAR MECHANISM LINKING SKELETAL MUSCLE AND VASCULAR DYSFUNCTION

Abstract

Recent decades of research have revealed that mitochondria play a crucial role not only in energy production but also in cellular signaling and fate determination. This article proposes the concept of the "mitochondrial–redox–immune axis" as an integrative molecular mechanism explaining the pathophysiological link between skeletal muscle and vascular dysfunction. Dysfunctions in the mitochondrial electron transport chain lead not only to energy deficiency but also to uncontrolled production of reactive oxygen species (ROS). This disruption of redox balance alters the functional polarization of inflammatory cells, particularly macrophages and T-lymphocytes, leading to chronic low-grade inflammation. In pathologies such as peripheral artery disease (PAD), chronic kidney disease (CKD), and heart failure (HF), the interplay of mitochondrial dysfunction, oxidative stress, and immune cell activation results in skeletal muscle atrophy, reduced contractile capacity, and endothelial dysfunction. Recent multi-omic studies, particularly the suppression of mitochondrial gene expression by uremic toxins (kynurenine, indoxyl sulfate), have been shown to contribute to muscle weakness. Additionally, mitochondrial dynamics in immune cells (e.g., Drp1 protein sulfenylation) and redox-sensitive signaling pathways (cGMP-PKG, NAMPT-NAD+) are crucial for vascular regeneration and muscle recovery under ischemic conditions. Identifying the molecular components of this axis lays the foundation for novel therapeutic approaches, including mitochondrial transplantation, antioxidant strategies, and immunomodulation, to treat interconnected diseases of skeletal muscle and vascular systems.