Pleiotropic effects of mitochondria in aging

Abstract

itochondria are evolutionarily derived from alphaproteobacteria that evolved in symbiosis within eukaryotic cells 1 . Although most alphaproteobacterial genes were transferred to the eukaryotic nucleus, mitochondria retained their genome to translate the remaining protein-coding genes within their DNA. This requires complex coordination of the transcription and translation from two genomes, and the import and processing of proteins into the mitochondria in an ever-changing cellular milieu 2,3 . Disruption of these finely controlled processes has been shown to impair cellular homeostasis. To cope with this downside of endosymbiosis, mitochondria have evolved multiple stress-response pathways. The mitochondrial stress-response (MSR) network contributes to the reconstitution of cellular homeostasis by preventing mitochondrial proteotoxicity and by redistributing and removing irreversibly damaged elements of the mitochondria 4 . In recent years, we have gained considerable insights into why a decline in the robustness of these MSR pathways contributes to cellular damage and organismal deterioration. This is underlined by our emerging understanding of how different types of mitochondrial defects are co-regulated and interact across cellular and systemic processes.Here, we describe the pleiotropic effects of mitochondrial dysfunction in aging. We outline the major mitochondrial stress pathways, how their failure is interconnected with the expansion of mitochondrial DNA mutations and deregulated metabolism, and how this affects cellular and organismal homeostasis. We furthermore provide an integrated map of how combined mitochondrial defects impact several features of aging, suggesting conserved links that could potentially be harnessed to slow the aging process. We refer readers to other comprehensive reviews on topics not covered in depth here, such as cellular senescence, stem cell function, and reactive oxygen species (ROS) [5][6][7] .

The Potential Implications of Hydrogen Sulfide in Aging and Age-Related Diseases through the Lens of Mitohormesis

“…Mitochondria are crucial to both physiology and pathophysiology, since their roles go beyond being the powerhouse of eukaryotic cells [ 63 ]. Literature has reported that mitochondrial function is declined with aging in humans [ 64 ], suggesting a connection between mitochondria with aging and age-related diseases [ 8 , 9 , 10 ]. A vicious cycle in which the increased ROS production induces mitochondrial dysfunction and vice versa is the basis of the free radical theory of aging proposed by Harman [ 11 ].…”

“…The activation of the mitochondrial unfolded protein response acts as the first line of defense for relieving the stress. However, when the stress level is overwhelming, mitochondrial dynamics and mitochondrial autophagy (mitophagy) come into action for the removal of a part of the mitochondria or the entire damaged mitochondria, respectively [ 9 , 10 ]. It has been proposed that any defect in how the mitochondria sense and respond to a stress is critical for the initiation and progression of aging and age-related diseases [ 65 , 66 ], highlighting the potential implications of mitohormesis in maintaining mitochondrial function and promoting healthy aging.…”

“…In response to the accumulation of unfolded or misfolded proteins exceeding the chaperone protein-folding capacity of mitochondria, UPR mt is activated to induce a retrograde signaling pathway from the mitochondria to the nucleus, leading to the expression of proteases, chaperonins, and many stress response genes to degrade the unfolded or misfolded proteins, increase the chaperone capacity, and re-establish the mitochondrial protein homeostasis [ 71 ]. Literature has also indicated that a disruption of mitochondrial proteostasis plays an important role in the UPR mt activation that has crucial implications in aging [ 10 ]. For example, an increased protein-folding workload in the mitochondria as a proteostatic stress may trigger the UPR mt activation in C. elegans [ 72 ].…”

“…Suggestive of potential relevance in mammals, the UPR mt network is also active in various tissues [ 73 ], which is deregulated in age-related diseases such as sarcopenia (muscle wasting and weakness) [ 74 ] and Alzheimer’s disease [ 75 , 76 ]. In addition, mitochondrial stresses can lead to the production of stress response molecules termed mitokines; some of them are expressed in response to UPR mt , such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) [ 10 ]. Both mitokines have shown many beneficial effects, including cardioprotective, neuroprotective, metabolic, anti-inflammatory, and anti-immunosenescent activities [ 77 , 78 , 79 , 80 ].…”

“…Mitochondria are vital organelles in eukaryotic cells, prominent for their crucial roles in energy production through the process of oxidative phosphorylation and in many other cellular processes, such as metabolisms, reactive oxygen species (ROS) generation, calcium homeostasis, apoptosis, and many more [ 7 ]. There is increasing evidence to indicate that a decline in the mitochondrial quality and activity is intricately linked to aging, contributing to the development of a wide range of age-related diseases [ 8 , 9 , 10 ]. The connection between mitochondria and aging has been widely explained by the free radical theory of aging originally proposed by Denham Harman in 1956, which hypothesized that the accumulation of oxidative damage generated by ROS is a key driver of aging [ 11 ].…”