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

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.