Cellular redox imbalance on the crossroad between mitochondrial dysfunction, senescence, and proliferation

Abstract

Recent studies demonstrate that redox imbalance of NAD⁺/NADH and NADP⁺/NADPH pairs due to impaired respiration may trigger two "hidden" metabolic pathways on the crossroad between mitochondrial dysfunction, senescence, and proliferation: "β-oxidation shuttle" and "hydride transfer complex (HTC) cycle". The "β-oxidation shuttle" induces NAD⁺/NADH redox imbalance in mitochondria, while HTC cycle maintains the redox balance of cytosolic NAD⁺/NADH, increasing the redox disbalance of NADP⁺/NADPH. Senescence appears to depend on high cytoplasmic NADH but low NADPH, while proliferation depends on high cytoplasmic NAD⁺ and NADPH that are under mitochondrial control. Thus, activating or deactivating the HTC cycle can be crucial to cell fate - senescence or proliferation. These pathways are a source of enormous cataplerosis. They support the production of large amounts of NADPH and intermediates for lipid synthesis and membrane biogenesis, as well as for DNA synthesis.