Commentary on a Connection Between Mitochondrial Dysfunction and Cellular Senescence

Last year, researchers demonstrated a link between mitochondrial dysfunction and cellular senescence, both implicated as mechanisms of aging. It isn't clear at this stage whether the link demonstrated is relevant in normal aging, as the senescent state produced through induced mitochondrial dysfunction doesn't appear to be the same as that observed in naturally aged tissues, but it is nonetheless quite intriguing. Here is a commentary on that research from one of the scientists involved:

Mitochondria are the primary source of energy (largely in the form of ATP) for most of our cells. They also more closely resemble bacteria than they do other parts of the cell. In fact, they have their own unique genome that, much like bacteria, is circular. Moreover, our mitochondrial DNA acquires mutations much more rapidly than our nuclear genome - due to a combination of weaker DNA repair and close proximity to reactive oxygen species (ROS) produced by respiration. These and other factors result in a state in which mitochondria become less and less functional as we age, a term generically called "mitochondrial dysfunction".

We show that cells with mitochondrial dysfunction undergo cellular senescence - a tumor-suppressive process that permanently halts cell division. However, these senescent cells lack many of the secretory features of the other types of senescence that we and others have studied. Cells that undergo mitochondrial dysfunction-associated senescence (MiDAS) secrete many biologically active factors, but they don't produce many of the typical inflammatory molecules produced by other forms of senescence. Instead, these cells secrete their own unique blend of biologically active factors that prevent adipogenesis and promote skin cell differentiation. In a model of mice that age prematurely due to mitochondrial mutations, MiDAS cells accumulate in fat deposits and skin, causing the mice to lose fat, lose hair, and develop very thin skin as they age.

Mechanistically, MiDAS occurred due to decreased cytosolic NAD+/NADH ratios. Mitochondria oxidize NADH to NAD+ as part of normal respiration, so when mitochondria are compromised NADH levels rise in the cell. As a consequence of lower NAD+/NADH ratios, AMP and ADP rise, leading to activation of AMP-activated protein kinase (AMPK), which then phosphorylates and activates p53 - a major mediator of senescence. Therefore, senescence is a natural outcome of metabolic stress following mitochondrial compromise. NADH can be oxidized by alterative means - and addition of factors such as pyruvate to the culture media allowed mitochondria-independent enzymes to oxidize NADH, restoring the NAD+/NADH ratio. When cultured in the presence of these compounds, cells with mitochondrial dysfunction grew normally and did not senesce. Surprisingly, these non-senescent cells had a secretome that largely resembled the canonical senescence-associated secretory phenotype (SASP)! Upon pyruvate withdrawal, these cells underwent senescence and lost their SASP-like secretome.

Many questions are still unanswered. Do MiDAS cells accumulate during normal aging? If so, where and when do they do so? Are NAD-targeted therapeutics still beneficial if they allow secretion of inflammatory factors? More importantly, can we target these cells to prevent or even cure some of the disorders associated with aging? Now that we know that MiDAS exists, we are positioned to answer these important questions.



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