Oncogene-induced senescence mitochondrial metabolism and bioenergetics drive the secretory phenotype: further characterization and comparison with other senescence-inducing stimuli

作者：Inés Marmisolle, Eliana Chacón, Santiago Mansilla, Santiago Ruiz, Mariana Bresque, Jennyfer Martínez, Ricardo Iván Martínez‐Zamudio, Utz Herbig, Jie Liu, Toren Finkel, Carlos Escande, Laura Castro, Celia Quijano · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103606 · 被引用次数：14 · 研究领域：Telomeres, Telomerase, and Senescence、Mitochondrial Function and Pathology、Autophagy in Disease and Therapy

Cellular senescence is characterized by proliferation arrest and a senescence-associated secretory phenotype (SASP), that plays a role in aging and the progression of various age-related diseases. Although various metabolic alterations have been reported, no consensus exists regarding mitochondrial bioenergetics. Here we compared mitochondrial metabolism of human fibroblasts after inducing senescence with different stimuli: the oxidant hydrogen peroxide (H 2 O 2 ), the genotoxic doxorubicin, serial passage, or expression of the H-RAS G12V oncogene (RAS). In senescence induced by H 2 O 2 , doxorubicin or serial passage a decrease in respiratory control ratio (RCR) and coupling efficiency was noted, in relation to control cells. On the contrary, oncogene-induced senescent cells had an overall increase in respiration rates, RCR, spare respiratory capacity and coupling efficiency. In oncogene-induced senescence (OIS) the increase in respiration rates was accompanied by an increase in fatty acid catabolism, AMPK activation, and a persistent DNA damage response (DDR), that were not present in senescent cells induced by either H 2 O 2 or doxorubicin. Inhibition of AMPK reduced mitochondrial oxygen consumption and secretion of proinflammatory cytokines in OIS. Assessment of enzymes involved in acetyl-CoA metabolism in OIS showed a 3- to 7.5-fold increase in pyruvate dehydrogenase complex (PDH), a 40% inhibition of mitochondrial aconitase, increased phosphorylation and activation of A...