Age is the largest risk factor for numerous pathologies, ranging from neurodegeneration to cancer. These pathologies likely arise from a loss of tissue homeostasis driven by one or more basic aging process, together with stochastic, genetic, and environmental factors. Mitochondria have long been hypothesized to be potential drivers of aging phenotypes, with dysfunctional mitochondria shown to accumulate with age in certain tissues. One consequence of this mitochondrial dysfunction is cellular senescence, a process whereby cells permanently lose the ability to divide.
The senescence response suppresses the development of cancer, however, there is mounting evidence that senescent cells can accumulate with age and cause or contribute to aging phenotypes and pathologies. Past studies show that dysfunctional mitochondria can induce cellular senescence in culture and in vivo. However, little is known about the mechanisms that mediate this effect. Now, a study from researchers at the Buck Institute Research has shown how cellular senescence is induced by signalling from dysfunctional mitochondria and how the arrested cells secrete a distinctly different ‘stew’ of biologically active factors in a process unrelated to the damaging free radicals that are also created in mitochondria. The team state that age researchers now need to stop thinking of cellular senescence as a single phenotype that stems from genotoxic stress. The opensource study is published in the journal Cell Metabolism.
Previous studies show that because mitochondria oxidize NADH to NAD+, mitochondrial dysfunction can decrease the NAD+/NADH ratio. While mitochondria oxidize NADH generated by fatty acid oxidation, they also oxidize the cytosolic NAD +/NADH. Lowering of the NAD+/NADH ratio via this reaction induces senescence, suggesting that elevated cytoplasmic NADH can drive cells into senescence. Notably, NAD+, an enzyme that is a co-factor for sirtuins, declines with age in several tissues, linking NAD to both senescence and aging. Therefore, in earlier studies, the lab screened sirtuins (SIRTs) that are linked to aging for ability to regulate senescence. The current study shows that the senescent phenotype only occurred when mitochondrial sirtuins were eliminated.
The current study shows that the senescent cells secreted a different senescence-associated secretory phenotype (SASP) than expected, specifically one that lacks the IL-1-dependent inflammatory arm. The group named this new phenomenon MiDAS- mitochondrial dysfunction-associated senescence. Results show that that mitochondrial dysfunction upset the balance of NAD+ which arrested cell growth and prevented the IL-1-associated SASP.
Data findings show that the NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell, highlighting a signaling role for mitochondria. The team note that this identifies a new type of SASP, underscoring the existence of different types of senescence.
The lab also observed the MiDAS SASP in mice genetically engineered to develop progeria in response to mitochondrial mutations, which causes rapid aging. Results show that the MiDAS SASP suppressed adipogenesis, which plays a vital role in metabolism and the creation of fat cells. The group state that their work provides a link to lipodystrophy, a medical condition characterized by abnormal or degenerative conditions involving fat tissue.
The team surmise that their findings are important in addressing mitochondrial diseases, and those age-related diseases, such as some forms of Parkinson’s, which involve mitochondrial dysfunction. For the future, the researchers state that for any disease that has a mitochondrial component their research adds a potential explanation for the real driver of the dysfunction, not involving free radicals, which they ruled out in their study. They go on to conclude that their data suggest a new role for mitochondria when it comes to affecting physiology.
Source: The Buck Institute
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