Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation

      Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from energy substrates to oxygen to produce adenosine triphosphate. Mitochondria also regulate cell proliferation, metastasis, and deterioration. The flow of electrons in the mitochondrial respiratory chain generates reactive oxygen species (ROS), which are harmful to cells at high levels. Oxidative stress caused by ROS accumulation has been associated with an increased risk of cancer, and cardiovascular and liver diseases. Glutathione (GSH) is an abundant cellular antioxidant that is primarily synthesized in the cytoplasm and delivered to the mitochondria. Mitochondrial glutathione (mGSH) metabolizes hydrogen peroxide within the mitochondria. A long-term imbalance in the ratio of mitochondrial ROS to mGSH can cause cell dysfunction, apoptosis, necroptosis, and ferroptosis, which may lead to disease. This study aimed to review the physiological functions, anabolism, variations in organ tissue accumulation, and delivery of GSH to the mitochondria and the relationships between mGSH levels, the GSH/GSH disulfide (GSSG) ratio, programmed cell death, and ferroptosis. We also discuss diseases caused by mGSH deficiency and related therapeutics. Mitochondria play a central role in maintaining cellular energy metabolism and viability. Through oxidative phosphorylation, electrons are transferred from metabolic substrates to molecular oxygen to generate adenosine triphosphate (ATP). In addition to energy production, mitochondria participate in the regulation of cellular proliferation, metabolic homeostasis, and aging processes. However, electron transfer within the mitochondrial respiratory chain also generates reactive oxygen species (ROS). Excessive ROS accumulation leads to oxidative stress and cellular damage and has been closely associated with the pathogenesis of cancer, cardiovascular disorders, and liver diseases.       Glutathione (GSH) is one of the most abundant intracellular antioxidants. It is primarily synthesized in the cytosol and subsequently transported into mitochondria through specific carrier systems. Mitochondrial glutathione (mGSH) plays a critical role in detoxifying hydrogen peroxide and maintaining mitochondrial redox homeostasis. Persistent imbalance between mitochondrial ROS production and mGSH levels can impair mitochondrial function and trigger multiple forms of programmed cell death, including apoptosis, necroptosis, and ferroptosis.          This review summarizes the physiological functions and biosynthetic pathways of GSH and examines its tissue distribution and mitochondrial transport mechanisms. Furthermore, we discuss the relationships between mGSH accumulation, the GSH/GSSG redox ratio, and programmed cell death pathways, particularly ferroptosis. Finally, diseases associated with mGSH deficiency and emerging therapeutic strategies targeting mitochondrial redox regulation are also discussed.