Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease

Abstract

Senescent cells, characterized by a state of irreversible proliferative arrest and inflammatory profile, have emerged as drivers of age-related decline. Growing evidence suggests that alterations in mitochondrial function and morphology play a key role in the induction and maintenance of senescence, as well as in promotion of the proinflammatory senescence-associated secretory phenotype (SASP). In this review, we seek to survey the relationship between mitochondrial dysfunction and senescence, focusing on the consequences of changes in oxidative phosphorylation efficiency, calcium handling, mitochondrial metabolites, mitochondrial dynamics and quality control, and release of damage-associated molecular patterns. We first describe these changes before illustrating the pathways and mechanisms through which mitochondrial dysfunction results in cell cycle arrest and the SASP. Lastly, we showcase evidence relating cellular senescence to neurodegenerative disease and propose that mitochondrial dysfunction may act as a bridge between the two.

Fig. 1. Mitochondrial dysfunction during cellular senescence aids proliferative arrest and enhances the SASP.

Mitochondrial membrane potential (ΔΨm) decreases during senescence as a result of accumulating calcium from the endoplasmic reticulum (ER) through mitochondria-ER contact sites (MERCS) and increased proton leakage. These and other changes decrease electron transport chain (ETC) efficiency, increasing reactive oxygen species (ROS) production and decreasing ATP production. An imbalance in the mitochondrial metabolites NAD⁺/NADH exacerbates declining ATP levels, promoting activation of AMPK. In addition to supporting cell cycle arrest, activated AMPK promotes mitochondrial biogenesis. Mitochondrial biogenesis and additional changes to morphological regulation, including increased mitochondrial fusion and decreased mitophagy, further aid ROS production. DNA damage caused by ROS enforces cell cycle arrest and promotes the SASP. In addition, ROS activates JNK, which promotes the formation of cytosolic chromatin fragments (CCFs), activating the cytosolic DNA sensor cGAS, which, through STING activation, enhances SASP production. Minority mitochondrial outer membrane permeabilization (miMOMP) releases inflammatory DAMPs, including mtDNA and cardiolipin, which further enhances the SASP.

Fig. 2. Mitochondrial dysfunction is a shared feature of cellular senescence and neurodegenerative disease.

The mitochondria of senescent cells and neural cells in the context of neurodegeneration exhibit a wide array of commonalities, including OXPHOS dysfunction leading to a loss of mitochondrial membrane potential (ΔΨm), increased ROS production, and altered energy metabolism characterized by reduced NAD⁺ and ATP levels. Mitochondrial calcium accumulation further exacerbates these changes. Mitophagy is also impaired which reduces mitochondrial quality. Lastly, damage-associated molecular pattern (DAMP) release promotes inflammation. These many shared features suggest mitochondrial dysfunction in neurodegenerative disease may be inducing senescence to further drive neurodegeneration.