Targeting mitochondrial transporters and metabolic reprogramming for disease treatment

In the realm of cellular biochemistry, mitochondria have been increasingly recognized for their critical role in both cellular metabolism and the etiology of various diseases. Mitochondrial transporters (MTs) are essential for maintaining cellular energy dynamics and metabolic fluxes by facilitating the bidirectional transfer of metabolites across mitochondrial membranes. Dysregulation of these transporters, such as the mitochondrial pyruvate carrier (MPC), citrate carrier (SLC25A1), and voltage-dependent anion channel (VDAC), disrupts energy metabolism, redox balance, and cellular signaling, contributing to the pathogenesis of neurodegenerative diseases (NDDs), cardiovascular diseases (CVDs), type 2 diabetes (T2D), and cancer. In NDDs, impaired transporters exacerbate oxidative stress and neuronal death, while in CVDs, they lead to energy deficits and heart failure. In T2D, dysfunctional transporters like MPC and carnitine palmitoyltransferase (CPT) systems drive insulin resistance and metabolic dysregulation. In cancer, upregulated transporters such as citrate carrier (SLC25A1), and dicarboxylate carrier (SLC25A10) as well as metabolic shifts like the Warburg effect support tumor growth and survival. Targeting MTs and metabolic reprogramming (MR) offers significant therapeutic potential. Preclinical studies have demonstrated the efficacy of mitochondrial-targeted therapies (MTT), such as adenosine monophosphate-activated protein kinase (AMPK) activators and antioxidants, in restoring metabolic homeostasis and reducing disease pathology. In cancer, inhibitors of glutamine transporters and VDAC1 are being explored to disrupt tumor metabolism. Several therapies are advancing to clinical trials, including mitochondrial-targeted drugs for NDDs and metabolic modulators for T2D and cancer, highlighting their translational potential. Despite notable individual achievements and isolated reviews in this field, there remains a lack of comprehensive syntheses that integrate these advancements. This review seeks to combine the prevailing scientific evidence and outline prospective research trajectories. The gathered data robustly support the significant potential of targeting MTs as a groundbreaking approach in the treatment of complex diseases, with the potential to significantly improve health outcomes and mitigate disease progression.