Impact of aldehyde dehydrogenase 2 deficiency on tissue-specific mitochondrial metabolism in aging mice

Age-related diseases arise from prolonged exposure to genetic and/or environmental factors, ultimately leading to cumulative and irreversible degeneration of tissues and the organism as a whole. We previously reported that accumulation of mitochondrially-generated aldehydes (i.e., 4-hydroxynonenal and acetaldehyde) causes mitochondrial dysfunction and accelerates the progression of age-related diseases. However, the contribution of mitochondrial aldehyde metabolism to aging (via aldehyde dehydrogenase 2, ALDH2) remains elusive. Here, we provide a comprehensive analysis of aldehyde metabolism and mitochondrial bioenergetics across different tissues in aging mice. We also address how mitochondrial function is influenced by the highly prevalent human inactivating ALDH2 E504K point mutation (ALDH2E504K) during aging. The liver metabolism was relatively resilient to aging, showing enhanced ALDH2 activity and improved mitochondrial coupling. Strikingly, aging-associated liver resilience was lost in ALDH2E504K mice. Aged hearts exhibited mixed outcomes including impaired mitochondrial basal respiration, improved ADP-driven respiration, and decreased ALDH2 detox capacity. The ALDH2E504K mutation exacerbated the already impaired cardiac ALDH2 detox capacity in aging. Strikingly, aging brain displayed pronounced vulnerability, with decreased ALDH2 activity, impaired mitochondrial bioenergetics and defective ALDH2 detox capacity. These changes were paralleled by impaired cognitive and behavioral functions in aged mice. As proof of concept, either the presence of ALDH2E504K mutation or acute ethanol challenge worsened cognitive and behavioral dysfunction in aging mice. Finally, we assessed in vitro efficacy of pharmacological ALDH2 activation in aging tissues. Collectively, these findings unravel the contribution of ALDH2E504K mutation to mitochondrial metabolism during aging; highlighting the detrimental synergy between genetic ALDH2 deficiency and aging in brain metabolism and physiology.