Campos-Ribeiro, M. A. | bioRxiv Science

bioRxiv2026

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.

molecular biology↗

bioRxiv2025

Mutant CHCHD10 disrupts cytochrome c oxidation and activates retrograde signaling in a model of cardiomyopathy.

Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause multi-systemic mitochondrial disease. Heterozygous Chchd10 knock-in mice modeling the human CHCHD10S59L variant associated with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) develop a mitochondrial cardiomyopathy driven by CHCHD10 insolubility and aggregation, which is associated with chronic activation of the mitochondrial integrated stress response (mtISR). Here, we demonstrate that cardiac dysfunction in Chchd10S55L/+ mice carrying the orthologous pathogenic variant is associated with dual defects originating at the onset of disease: (1) early bioenergetic dysfunction linked to defects in the mitochondrial copper homeostasis and the oxidation of cytochrome c and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using Oma1E324Q/E324Qknock-in mice, we show that the catalytic inactivation of the mitochondrial protease OMA1 in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, proteomic remodeling, cristae defects or OXPHOS impairment, demonstrating that mtISR can be uncoupled from the bioenergetic collapse triggered by mutant CHCHD10. Proteomic profiling of soluble and insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals wide-spread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria could be rescued by the exogenous addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Our work reveals that mutant CHCHD10 insolubility compromises metabolic resilience by impairing both mitochondrial bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.

cell biology↗