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American Heart Association

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Final ID: Mo107

Age-Related Impairment of Mitochondrial Protein Turnover Exacerbates Pathogenesis of Heart Failure with Preserved Ejection Fraction in Old Mice

Abstract Body: Introduction: Age is recognized as a major risk factor for heart failure with preserved ejection fraction (HFpEF), yet the precise role of aging in HFpEF development remains unknown. Disruption of mitochondrial protein turnover affects the quality and quantity of proteins crucial for energy metabolism. Although mitochondrial dysfunction is a key feature of both aging and HFpEF heart, the influence of age-related disturbances in mitochondrial protein turnover on HFpEF pathogenesis remains unclear.
Hypothesis: Age-related impairment of mitochondrial protein turnover intensifies proteostatic perturbations induced by hypertensive and metabolic stress (2-hit stress) to exacerbate pathogenesis of cardiometabolic HFpEF.
Methods: Young (3 mo.) and old (19 mo.) C57BL/6J male mice were exposed to high-fat diet and L-NAME to induce HFpEF development. Deuterium oxide (D2O) labeling coupled with mass spectrometry was used to investigate bulk and individual mitochondrial protein synthesis. The changes in individual mitochondrial protein abundance and protein degradation pathways were also studied.
Results: Old mice presented exacerbated HFpEF characteristics compared to young mice, with higher mortality and worsened cardiac and extra-cardiac phenotypes. Regardless of age, mice subjected to 2-hit stress had 24% higher bulk mitochondrial protein synthesis compared to controls. Old control and HFpEF mice showed 17% lower mitochondrial protein synthesis compared to younger counterparts, potentially hindering the replacement of dysfunctional mitochondrial proteins. Aging reduced the synthesis rates of 30 out of 115 proteins synthesized more rapidly with HFpEF, including those involved in mitochondrial metabolism. Despite slower synthesis of numerous mitochondrial proteins with age, the overall abundance of these proteins remained unchanged or elevated compared to young counterparts, indicating impaired protein degradation. We found that aging and 2-hit stress differentially inhibited degradation pathways, including autophagy and the ubiquitin-proteasome system, further impairing protein turnover.
Conclusion: Aging impairs mitochondrial protein turnover in cardiometabolic HFpEF and contributes to poorer disease outcomes.
  • Kobak, Kamil  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • Zarzycka, Weronika  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • King, Catherine  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • Borowik, Agnieszka  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • Peelor, Frederick  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • Kinter, Michael  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • Miller, Benjamin  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • Chiao, Ying Ann  ( Oklahoma Medical Research Foundatio , Oklahoma City , Oklahoma , United States )
  • Author Disclosures:
    Kamil Kobak: DO NOT have relevant financial relationships | Weronika Zarzycka: DO NOT have relevant financial relationships | Catherine King: DO NOT have relevant financial relationships | Agnieszka Borowik: No Answer | Frederick Peelor: No Answer | Michael Kinter: No Answer | Benjamin Miller: No Answer | Ying Ann Chiao: DO NOT have relevant financial relationships
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception I

Monday, 07/22/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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mtNAD+ Depletion in Cardiomyocytes Disrupts Postnatal Metabolic Adaptations and Leads to Lethal Eccentric Cardiac Hypertrophy

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Cardiac-specific mTORC1 Suppression Protects Against the Development of Heart Failure with Preserved Ejection Fraction

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