Cell aging attenuates cellular functions, resulting in time-dependent disruption of cellular homeostasis, which maintains the functions of proteins and organelles. Mitochondria are important organelles responsible for cellular energy production and various metabolic processes, and their dysfunction is strongly related to the progression of cellular aging.

Appropriate mitochondrial function relies on interactions with other organelles, such as the endoplasmic reticulum. To gain an understanding of this process, we initially examined the cellular events transpiring during the time-dependent alterations associated with cellular aging. Our findings demonstrated that disruption of proteostasis attenuates mitochondrial function before the induction of DNA damage signaling by proliferative and replicative cellular aging. Consequently, to identify a compound capable of ameliorating age-related proteostasis abnormalities and restoring mitochondrial function, we found that the induction of autophagy via activating the DAPK1-Beclin1 signaling pathway effectively clears abnormal proteins and agglutinates, ultimately leading to the restoration of both mitochondrial function and cellular aging phenotypes. Therefore, time-dependent accumulation of abnormal proteins and agglutinates suppressed mitochondrial function in cells in the early stage of aging, and reactivation of mitochondrial function by restoring proteostasis rejuvenated aging cells.

1. Machihara K, Kageyama S, Oki S, Makino H, Sasaki M, Iwahashi H and Namba T *. (2022) Lotus germ extract rejuvenates aging fibroblasts via restoration of disrupted proteostasis by the induction of autophagy. Aging. 26, 7662-7691.

2. Namba, T*. (2019) BAP31 regulates mitochondrial function via interaction with Tom40 within ER-mitochondria contact sites. Science Advances 5, eaaw1386.