Lipid Metabolism, Mitochondrial Stress, and Senescence

Project Abstract Accumulation of senescent cells in adipose tissue, particularly visceral depots, is increasingly becoming more appreciated as a causal factor in age- and obesity-associated metabolic dysfunction, conditions that impart a heavy burden in terms of suffering and mortality on public health. Concomitant creation of an inflammatory milieu is thought to facilitate the development of systemic insulin resistance. As lipid peroxidation and pertinent drivers are shown to be associated with lifespan and age-related pathologies, I posit that resulting electrophilic lipid byproducts can incite or potentiate senescence in adipose. Produced abundantly in adipocytes by peroxidation of mitochondrial phospholipids, lipid aldehydes such as 4-hydroxynonenal (HNE) and 4-oxo-2-nonenal (ONE) covalently modify nucleophilic protein residues and herein I hypothesize that carbonyl stress exerts oxidative stress and mitochondrial dysfunction to induce the senescence program in adipose progenitor cells. Proposed studies would represent the first efforts to thoroughly and systematically characterize the biochemistry and cellular signaling underpinning cellular senescence brought on by lipid aldehydes. IMR90 fibroblasts continuously exposed to lipid aldehydes for seven days exhibit initiation of the senescence program, characterized by induction of SA-β-gal activity and enhanced expression of CDKN1A (p21Cip1), among other senescence markers. I’ve termed this type of senescence Biogenic Lipid Induced Senescence, BLIS. Associated with BLIS is the upregulation of an NFκB-independent subset of the putative human SASP. Furthermore, I demonstrated that permeabilization of mitochondrial membranes by BAK/BAX channels mediate the BLIS phenotype. The overall mechanism of lipid aldehyde associated senescence is multifaceted and likely to involve mitochondrial protein modification, as I observed hallmarks of aberrant mitochondrial function concomitant with development of BLIS markers and alkylation of mitochondrial proteins. Indeed, 4-HNE exposure effects reduced mitochondrial spare capacity and increased ADP:ATP ratios. Taken together, preliminary data suggest that reactive lipid aldehydes can induce cellular senescence and that adipose senescence may be linked to lipid-mediated senescence induction in fat tissue. Proposed work can be broken down into two aims: in my first aim, I will use a proteomics-based approach to define targets of mitochondrial carbonylation during obesity and aging and in my second aim, I will investigate the role of mitochondrial stress and signaling on adipose senescence. During proposed experiments, I will build vital skills as a researcher, most importantly in proteomics data analysis and hands-on in vivo work with mouse models. Backed by a mentoring committed composed of faculty active in the field of aging research and spanning multiple departments at the University of Minnesota, I am confident an F32 fellowship will facilitate both my development as a researcher and novel, impactful research.