Tetraploidy in normal tissues and diseases: mechanisms and consequences

Tetraploidisation plays a crucial role in evolution, development, stress adaptation, and disease, but its beneficial or pathological effects in different tissues remain unclear. This study aims to compare physiological and unphysiological tetraploidy in eight steps: 1) mechanisms of diploidy-to-tetraploidy transition, 2) induction and elimination of unphysiological tetraploidy, 3) tetraploid cell characteristics, 4) stress-induced unphysiological tetraploidy, 5) comparison of physiological vs. unphysiological tetraploidy, 6) consequences of unphysiological stress-induced tetraploidy, 7) nutritional or pharmacological prevention strategies of tetraploidisation, and 8) knowledge gaps and future perspectives. Unphysiological tetraploidy is an adaptive stress response at a given threshold, often involving mitotic slippage. If tetraploid cells evade elimination through apoptosis or immune surveillance, they may re-enter the cell cycle, causing genetic instability, micronuclei formation, aneuploidy, modification of the epigenome and the development of diseases. The potential contributions of unphysiological tetraploidy to neurodegenerative, cardiovascular and diabetes related diseases are summarized in schematic figures and contrasted with its role in cancer development. The mechanisms responsible for the transition from physiological to unphysiological tetraploidy and the tolerance to tetraploidisation in unphysiological tetraploidy are not fully understood. Understanding these mechanisms is of critical importance to allow the development of targeted nutritional and pharmacological prevention strategies and therapies.