Defective dimerization of FoF1‐ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging

Abstract

Aged cardiomyocytes develop a mismatch between energy demand and supply, the severity of which determines the onset of heart failure, and become prone to undergo cell death. The FoF1‐ATP synthase is the molecular machine that provides >90% of the ATP consumed by healthy cardiomyocytes and is proposed to form the mitochondrial permeability transition pore (mPTP), an energy‐dissipating channel involved in cell death. We investigated whether aging alters FoF1‐ATP synthase self‐assembly, a fundamental biological process involved in mitochondrial cristae morphology and energy efficiency, and the functional consequences this may have. Purified heart mitochondria and cardiomyocytes from aging mice displayed an impaired dimerization of FoF1‐ATP synthase (blue native and proximity ligation assay), associated with abnormal mitochondrial cristae tip curvature (TEM). Defective dimerization did not modify the in vitro hydrolase activity of FoF1‐ATP synthase but reduced the efficiency of oxidative phosphorylation in intact mitochondria (in which membrane architecture plays a fundamental role) and increased cardiomyocytes’ susceptibility to undergo energy collapse by mPTP. High throughput proteomics and fluorescence immunolabeling identified glycation of 5 subunits of FoF1‐ATP synthase as the causative mechanism of the altered dimerization. In vitro induction of FoF1‐ATP synthase glycation in H9c2 myoblasts recapitulated the age‐related defective FoF1‐ATP synthase assembly, reduced the relative contribution of oxidative phosphorylation to cell energy metabolism, and increased mPTP susceptibility. These results identify altered dimerization of FoF1‐ATP synthase secondary to enzyme glycation as a novel pathophysiological mechanism involved in mitochondrial cristae remodeling, energy deficiency, and increased vulnerability of cardiomyocytes to undergo mitochondrial failure during aging.

"Age-Related Variations of the Brain Mitochondrial Permeability Transition Pore and Complex I in Response to Hypoxia"

“…However, the influence of aging on ATP synthase and its role in mPTP functioning and/ or regulation has not been investigated yet. Studies with mice [71] and rats [55] show that the abundance of most of the ATP synthase subunits stays constant during aging. However, other factors such as oligomerization and post-translational modifications of subunits of ATP synthase may change with age and alter the activity of this complex [71,72].…”

“…Studies with mice [71] and rats [55] show that the abundance of most of the ATP synthase subunits stays constant during aging. However, other factors such as oligomerization and post-translational modifications of subunits of ATP synthase may change with age and alter the activity of this complex [71,72]. It has been suggested that age-associated glycation of ATP synthase constituents as well as reduced dimerization and oligomerization of ATP synthase increase the susceptibility of mPTP to Ca 2+ [71].…”

“…However, other factors such as oligomerization and post-translational modifications of subunits of ATP synthase may change with age and alter the activity of this complex [71,72]. It has been suggested that age-associated glycation of ATP synthase constituents as well as reduced dimerization and oligomerization of ATP synthase increase the susceptibility of mPTP to Ca 2+ [71]. In addition, other post-translational modifications of ATP synthase such as phosphorylation [73,74] and nitration [75] have been described during aging, but their role in mPTP functioning or regulation is still unclear [76].…”

Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology

“…Also, aging was found to be related to altered cristae morphology. Thus, ATP-synthase dimerization was found to be disrupted with concominant alternations in cristae morphology in aged mice (Bou-Teen et al, 2022 ; Daum et al, 2013 ) and Podospora anserina (Warnsmann et al, 2021 ). Numerous findings in lower organisms supported the idea of adjusted cristae morphology in aging.…”

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning

“…Not only does it increase the vulnerability of the heart to IRI, but it also hampers the therapeutic efficiency of several ischemic and pharmacologic conditioning strategies in many (but not all) experimental models and in some clinical studies, as recently reviewed ( Ruiz-Meana, Boengler, et al, 2020 ; Ruiz-Meana, Bou-Teen, et al, 2020 ). The loss of cardioprotection during aging can be attributed to different factors, among them: (i) the higher burden of comorbidities (e.g., hypertension, metabolic disorders) that may impose additional damage to the heart ( Andreadou et al, 2021 ), (ii) the more frequent use of concomitant medications that can cause therapeutic interferences ( Ferdinandy et al, 2014 ), (iii) the coexistence of a chronic and deleterious proinflammatory myocardial environment ( Ramos et al, 2017 ), (iv) the progressive accumulation of damaged and dysfunctional mitochondria within cardiomyocytes ( Ruiz-Meana et al, 2019 ; Bou-Teen et al, 2022 ), and (v) the attenuation of some signaling pathways mechanistically involved in cell survival ( Boengler, Schulz, et al, 2009 ). The majority of studies have described a loss of ischemic PreC-induced cardioprotection with age, yet some authors reported myocardial protection by ischemic PreC in old rat hearts ( Webster et al, 2017 ).…”