Thursday, June 12, 2025
6/12/2025
Pathological cardiolipin remodeling links mitochondrial dysfunction to inflammaging - ABSTRACT Aging is characterized by progressive decline in tissue and organ function leading to increased risk of age-related diseases. Among diverse factors that contribute to aging, mitochondrial dysfunction and chronic, sterile, low-grade inflammation have emerged as the major hallmarks of aging process and are linked to the development of numerous age-related diseases. Emerging evidence suggests that the two phenomena are interrelated. In particular, circulating cell-free mitochondrial DNA (mtDNA) has been proposed as a functional link between mitochondrial damage and systemic inflammation, yet the underlying mechanisms remain largely unknown. Cardiolipin (CL) is a mitochondrial signature phospholipid that is required for mitochondrial membrane structure, dynamics, biogenesis, and mitophagy. We and others have previously shown that the onset of aging causes pathological remodeling of CL by polyunsaturated fatty acids (PUFA). Enrichment of PUFA renders CL highly sensitive to oxidative damage, leading to CL depletion and mtDNA release. Our previous studies identified acyl-CoA lysocardiolipin acyltransferase 1 (ALCAT1) as a key enzyme that catalyzes the pathological remodeling of CL in age-related diseases. Defective CL remodeling by ALCAT1 leads to oxidative stress and mtDNA instability. Consequently, ablation of ALCAT1 effectively protected mice from the development of various age-related diseases. Our preliminary studies also identified a striking role of ALCAT1 in regulating cellular senescence and immune response in aging. ALCAT1 deficiency significantly attenuates high-fat-diet induced cellular senescence and mitigates lipopolysaccharide induced inflammation in mice. In contrast, overexpression of ALCAT1 causes cytoplasmic release of mtDNA and activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS -STING) pathway. Strikingly, ablation of ALCAT1 extends the lifespan of normal mice and the mitochondrial DNA polymerase γ (Polg) D257A mutator mice (Polgm/m), a premature aging mouse model. These exciting findings lead us to hypothesize that pathological CL remodeling by ALCAT1 promotes inflammaging by activating the cGAS-STING pathway through stimulation of cytosolic mtDNA release. By using the aging mice models and primary cells, the hypothesis will be tested by two specific aims: Aim1 will determine whether ALCAT1 causes cellular senescence and inflammaging by promoting mitochondrial dysfunction through pathological CL remodeling; Aim2 will identify the underlying molecular mechanisms by which pathological CL remodeling link mitochondrial dysfunction to inflammaging. The completion of the proposed studies is expected to provide key insights on pathological CL remodeling by ALCAT1 in mediating mitochondrial dysfunction, cellular senescence and inflammaging, which will lay a foundation to target ALCAT1 as a novel and potent treatment for age-related diseases.
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