Targeting mitochondrial transporters and metabolic reprogramming for disease treatment

Abstract

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.

Keywords: Cellular metabolism; Disease treatment; Metabolic reprogramming; Mitochondria; Mitochondrial transporters.

Fig. 1

Overview on dysfunction of MTs and metabolic switch in neurodegenerative diseases. Note that pathophysiologic phenomena are more complex than depicted. Genetic mutations affecting mitochondrial solute carriers, such as SLC25A19 and SLC25A20, result in compromised substrate translocation, diminished adenosine triphosphate (ATP) synthesis, and elevated levels of reactive oxygen species (ROS). Furthermore, specific transporters, including SLC25A10, SLC25A17, and SLC25A22, have been implicated in Alzheimer's disease (AD) predisposition; notably, SLC25A22 dysfunction induces glutamate excitotoxicity and hippocampal atrophy. Deficiencies in adenine nucleotide translocase (SLC25A4) activity and voltage-dependent anion channel (VDAC) dysfunction disrupt mitochondrial energy metabolism and calcium homeostasis. Accumulation of amyloid-beta (Aβ) within mitochondria impairs glucose and pyruvate transport, calcium signaling, and mitochondrial dynamics, manifesting as an imbalance in fission and fusion processes, leading to mitochondrial fragmentation. AD is characterized by a reduction in cerebral glucose utilization, which correlates with diminished activity of tricarboxylic acid (TCA) cycle enzymes, including pyruvate dehydrogenase complex (PDHc) and α-ketoglutarate dehydrogenase complex (KGDHc). Additional factors contributing to neuronal damage in AD encompass dysregulation of mitochondrial dynamics and aberrant mitochondrial permeability transition pore (mPTP) function

Fig. 2

Overview on mitochondrial transporters and metabolic switch in failing heart. Note that pathophysiologic phenomena are more complex than depicted. Impairments in specific mitochondrial transporters (MTs) such as adenine nucleotide translocase (ANT), mitochondrial phosphate carrier (PiC), and citrate carrier (CIC) lead to reduced ATP synthesis, resulting in energy deficits that contribute to heart failure. Dysregulation of the mitochondrial calcium uniporter (MCU) and sodium-calcium exchanger 1 (NCX1) is associated with cardiac issues like arrhythmias, hypertrophy, and heart failure. Additionally, decreased fatty acid oxidation (FAO) due to deficiencies in carnitine palmitoyltransferase 1 (CPT1) and the carnitine-acylcarnitine carrier (CAC) leads to increased lipid accumulation and mitochondrial dysfunction. MTs also play a role in maintaining redox balance; their dysfunction causes elevated reactive oxygen species (ROS) production and oxidative stress. Overall, disruptions in mitochondrial transporter function significantly contribute to cardiomyocyte apoptosis, fibrosis, and necrosis, which are critical features of cardiac hypertrophy and heart failure progression

Fig. 3

Overview on impaired mitochondrial transporter proteins and metabolism in T2D. Note that the pathophysiologic phenomenon is more complex than here depicted. Dysfunction in key mitochondrial transporters—such as the mitochondrial pyruvate carrier (MPC), carnitine palmitoyltransferase (CPT) system, and citrate and dicarboxylate carriers—disrupts glucose and fatty acid metabolism, leading to ATP depletion, metabolite accumulation, oxidative stress, and inflammation. Additionally, impaired mitochondrial calcium handling and disruptions in the electron transport chain (ETC) exacerbate mitochondrial stress and insulin resistance. Regulatory pathways, including AMPK and SIRT1 signaling, also influence mitochondrial function and metabolic homeostasis. These molecular disturbances collectively contribute to the pathophysiology of T2D

Fig. 4

Overview on mitochondrial transporters and metabolic switch in cancer cells. Note that the pathophysiologic phenomenon is more complex than here depicted. Alterations in MTs, such as VDAC1, SLC25 family proteins, and glutamine transporters, contribute to tumor growth, metabolic adaptation, and resistance to stress. Upregulated transporters like citrate carrier (CIC) and dicarboxylate carrier (DIC) facilitate bioenergetics, lipid biosynthesis, and redox homeostasis, correlating with tumor aggressiveness and poor prognosis. The metabolic shift from OXYPHOS to glycolysis supports cancer cell survival, while mitochondrial calcium regulation and permeability transition pores (PTPs) influence cell fate