Exploring the potential role of monocarboxylate transporters in statin-induced mitochondrial dysfunction: a new perspective on statin-related myopathy and anti-cancer strategies

Abstract Background Statins are widely prescribed for their lipid-lowering effects, yet their association with mitochondrial dysfunction remains a significant clinical concern. Although the mechanisms underlying statin-induced mitochondrial effects have been extensively studied, the role of monocarboxylate transporters (MCTs) in this process has not been directly examined. While direct evidence is limited, emerging data suggests a plausible intersection. We propose a novel hypothesis that statin-mediated modulation of MCT activity may alter lactate transport and mitochondrial energetics via non-classical pathways, offering a new perspective on the pathophysiology of statin-related myopathy (SRM). Main body This review synthesizes current evidence on how statins may interfere with lactate transport, potentially impacting the regulation of mitochondrial genes or pathways across cellular environments including, but not limited to, skeletal muscle. Drawing from both in vitro and in vivo studies, two key observations emerge: (i) statins are capable of impairing mitochondrial function, and (ii) MCTs are essential for maintaining mitochondrial function by regulating the flux of lactate and other monocarboxylates. Emerging research indicates that impaired lactate transport, particularly through inhibition of MCT1 and MCT4, may contribute to mitochondrial dysfunction in muscle tissues. This disturbance compromises the activity of mitochondrial complex I and III, triggering a cascade of metabolic consequences: impaired oxidative metabolism, reduced ATP production and elevated production of reactive oxygen species. Furthermore, SRM have been linked to diminished mitochondrial DNA (mtDNA) content and dysregulation of key genes governing mitochondrial homeostasis and biogenesis (such as mtDNA, PGC-1α, SOD1, SOD2), dynamics (MFN2, FIS1) and oxidative phosphorylation (CPT2, Complex I-IV). Notably, modulating MCT function has emerged as a promising strategy for repurposing statins as anticancer agents. Dysregulation of MCT activity by statins has been implicated in cancer cell survival, proliferation, and metabolic reprogramming. Conclusion Clarifying MCT involvement in statin-induced mitochondrial dysfunction has expanded our perspective into both adverse effects and anti-cancer potential of statins, inspiring new strategies in translational cardiovascular medicine and oncology research. This conceptual framework highlights the need for integrative studies bridging MCT biology with mitochondrial pharmacotoxicology.