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.