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

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Pathways

Background:

• Mitochondrial dysfunction and impaired respiration can lead to redox imbalance in NAD+/NADH and NADP+/NADPH pairs.
• This imbalance may activate two critical metabolic pathways: the "β-oxidation shuttle" and the "hydride transfer complex (HTC) cycle".

Purpose of the Study:

• To elucidate the roles of the "β-oxidation shuttle" and "HTC cycle" in cellular processes.
• To investigate the connection between these pathways, mitochondrial dysfunction, senescence, and proliferation.
• To understand how manipulating the HTC cycle influences cell fate.

Main Methods:

• Analysis of redox states of NAD+/NADH and NADP+/NADPH.
• Investigation of mitochondrial function and cellular respiration.
• Assessment of senescence and proliferation markers.
• Evaluation of metabolic flux through the identified pathways.

Main Results:

• The "β-oxidation shuttle" disrupts mitochondrial NAD+/NADH redox balance.
• The HTC cycle maintains cytosolic NAD+/NADH redox balance but increases NADP+/NADPH redox disbalance.
• Cellular senescence is associated with high cytoplasmic NADH and low NADPH.
• Cellular proliferation requires high cytoplasmic NAD+ and NADPH, regulated by mitochondria.
• These pathways contribute significantly to cataplerosis, supporting NADPH and lipid/DNA synthesis.

Conclusions:

• The HTC cycle plays a crucial role in determining cell fate, dictating whether a cell undergoes senescence or proliferation.
• Mitochondrial control over cytosolic redox balance is essential for regulating cell proliferation.
• Targeting the HTC cycle offers a potential strategy for controlling cell fate in various biological contexts.