Mitochondrial Toxicology of Heavy Metals and Pesticides: Transport Systems, Mitochondrial Dysfunction and...

Mitochondrial transport systems are essential regulators of cellular bioenergetics, calcium homeostasis, and metabolic signaling, and have emerged as critical targets of environmental toxicants. Although heavy metals and pesticides act through distinct primary mechanisms, increasing evidence indicates that they converge on a common network of mitochondrial dysfunction characterized by oxidative stress, impaired metabolite transport, calcium dyshomeostasis, and sensitization to mitochondrial permeability transition. This review provides an updated overview of the major mitochondrial transport systems involved in environmental toxicity, including the adenine nucleotide translocator (ANT), phosphate carrier (PiC), mitochondrial calcium uniporter (MCU), voltage-dependent anion channel (VDAC), and F1·Fo-ATP synthase (ATP synthase). We discuss their physiological roles, the molecular mechanisms by which heavy metals and pesticides disrupt their function, and the effects on oxidative phosphorylation, reactive oxygen species (ROS) generation, cardiolipin remodeling, and mitochondrial membrane integrity. Particular attention is devoted to the debate surrounding the molecular basis of mitochondrial permeability transition pore (mPTP) formation and to the concept that permeability transition represents the integrated outcome of cumulative mitochondrial stress rather than dysfunction of a single protein. Finally, we summarize emerging therapeutic strategies aimed at preserving mitochondrial transport function, limiting mitochondrial permeability transition, and attenuating downstream inflammatory signaling. Understanding these convergent mechanisms may facilitate the development of interventions to mitigate chronic diseases associated with environmental toxicant exposure.