A novel physiological role for mitochondria with implications in the study of age-related diseases such as Parkinson’s has been described. Researchers found that mitochondrial dysfunction in proliferating human cells induces senescence growth arrest and causes cells to secrete distinct secretory phenotypes. The research paper, titled “Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype,” was published in Cell Metabolism.
Cellular senescence, a response usually attributed to stress and damage from extracellular and endogenous sources — and an important driver of the aging process, is characterized by a permanent state of growth arrest and loss of the ability to divide. However, new research from Dr. Judith Campisi at the Buck Institute for Research on Aging indicates that signaling from dysfunctional mitochondria also induces senescence, with these cells secreting a different senescence-associated secretory phenotype (SASP). Dr. Campisi and her team happened upon this discovery were eliminating sirtuins, proteins involved in longevity, in human cell cultures. Elimination of mitochondrial sirtuins led to a senescent phenotype with a different SASP, lacking one of the major SASP factors previously identified, the IL-1-dependent inflammatory arm, a phenomenon the research team named MiDAS (mitochondrial dysfunction-associated senescence).
Dr. Campisi explained how this research might contribute to new therapies. “We don’t yet know how much this process contributes to natural aging. But we do think the findings are important in addressing mitochondrial diseases, and those age-related diseases, such as some forms of Parkinson’s, which involve mitochondrial dysfunction,” she said in a press release.
Furthermore, mitochondrial dysfunction also disrupted the balance of NAD+, an enzyme that is a co-factor of sirtuins, arresting cell growth and disrupting IL-1 dependent SASP. “The NAD+ balancing act happens outside the mitochondria in the cytoplasm of the cell. This really highlights a signaling role for mitochondria, something understudied in the context of disease. And it identifies a new type of SASP, underscoring the existence of different types of senescence,” said Dr. Christopher Wiley, PhD.
Studies in mice with dysfunctional mitochondria and premature aging showed accumulation of senescent cells and suppression of adipogenesis, an important cell metabolism and fat creation mechanism. According to the researchers, these results explain the lipodystrophy, or loss of subcutaneous fat, observed in patients taking early HIV drugs, which deplete mitochondrial DNA.
Dr. Campisi concluded, “For any disease that has a mitochondrial component, this research adds a potential explanation for the real driver of the dysfunction — and it’s not free radicals, which we ruled out in our study. Our findings suggest a new role for mitochondria when it comes to affecting physiology.”