Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Abstract

Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored. Here, we review some of the mitochondrial signaling pathways that participate in establishing cellular senescence. We discuss the role of mitochondrial reactive oxygen species (ROS), mitochondrial dynamics (fission and fusion), the electron transport chain (ETC), bioenergetic balance, redox state, metabolic signature, and calcium homeostasis in controlling cellular growth arrest. We emphasize that multiple mitochondrial signaling pathways, besides mitochondrial ROS, can induce cellular senescence. Together, these pathways provide a broader perspective for studying the contribution of mitochondrial stress to aging, linking mitochondrial dysfunction and aging through the process of cellular senescence.

Keywords: NAD; aging; bioenergetics; cellular senescence; electron transport chain; metabolism; mitochondria; reactive oxygen species.

Figure 1

Perturbation of mitochondrial homeostasis promotes the establishment and maintenance of cellular senescence during aging. Mitochondria are damaged over time leading to perturbation of mitochondrial homeostasis. Loss of proper mitochondrial homeostasis can promote cellular senescence through (1) excessive ROS production (orange), (2) impaired mitochondrial dynamics (brown), (3) electron transport chain defect (blue), (4) bioenergetics imbalance and increased AMPK activity (red), (5) decreased mitochondrial NAD+ and altered metabolism (green), and (6) mitochondrial calcium accumulation (purple). These mitochondrial signals trigger p53/p21 and/or p16/pRb pathways and ultimately lead to cellular senescence, which subsequently promotes age-related phenotypes, such as loss of tissue regeneration and function.