Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart
Year: 2025
Type: article
Abstract: Introduction: Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known. Aim: This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging. Methods and Results: We utilized 10- and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, Tfam ; however, selective mtDNA genes, such as mt-Cytb and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including Lonp1, Yme1l1, Afg3l2, and Spg7 , were significantly induced, with a substantial induction of Clpp and Clpx . However, age-associated differences were not observed in the induction of mt chaperones (Hspa9 and Hspd1 ), but significant induction of Dnaja2 , a mitochondrial co-chaperone, was observed. The ER stress transcription factors Xbp1 and Atf6 were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone Hsp90b with no change in Hspa5 and Dnajb9 chaperones. However, induction of Dnm1l was significant, whereas Mfn1 and Fis1 were downregulated in contrast to Mfn2 , suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels. Conclusion: These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.
DOI: 10.20517/jca.2024.17
Institutions: West Virginia University, Rutgers New Jersey Medical School
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: Mitochondrial protein quality control in cardioprotection, G5114740903, MITOCHONDRIA ARE THE POWERHOUSES OF THE CELL WHICH MAKE UP 30% OF THE VOLUME OF CARDIAC MYOCYTES. THEY PROVIDE THE CRUCIAL ENERGY SUPPLY NEEDED FOR THE HEART TO BEAT AND TO PROVIDE BLOOD AND OXYGEN THROUGHOUT THE BODY. THE GOAL OF THIS GROUND-BASED TISSUE SHARING PROJECT IS TO DETERMINE THE EFFECTS OF LOW DOSE/LOW FLUENCE SPACE IONIZING RADIATION ON THE MITOCHONDRIAL STRESS RESPONSE IN THE HEART. WE WILL EXAMINE HEART TISSUE COLLECTED BY OUR COLLABORATOR DR. EDOUARD AZZAM WHOSE CURRENT NASA-FUNDED PROJECT IS INVESTIGATING "OXIDATIVE STRESS AND THE CANCER RISK OF SPACE RADIATION". HIS STUDY EMPLOYS 10 MONTH-OLD MALE MICE WHICH IS AN AGE THAT IS EQUIVALENT TO ACTIVE ASTRONAUTS WHO ARE BETWEEN 35-55 YEARS OLD. THESE MICE ARE EXPOSED TO LOW MEAN ABSORBED DOSES OF ISOVELOCITY (1 GEV/N) PROTONS OR HIGH ATOMIC NUMBER HIGH ENERGY (HZE) PARTICLES WHICH ARE A COMPONENT OF GALACTIC COSMIC RAYS. ANOTHER GROUP OF MICE ARE EXPOSED TO 137CS "{RAYS AS REFERENCE RADIATION. USING THESE HEART SAMPLES WE WILL EMPLOY HISTOLOGICAL TECHNIQUES AS WELL AS BIOCHEMICAL AND MOLECULAR BIOLOGICAL APPROACHES TO MEASURE BIOMARKERS OF THE MITOCHONDRIAL STRESS RESPONSE IN HEART IN RESPONSE TO HZE PARTICLES AND REFERENCE RADIATION. CARDIAC INFLAMMATION AND FIBROSIS WILL BE EXAMINED HISTOLOGICALLY. RADIATION-INDUCED CHANGES IN MITOCHONDRIAL DNA COPY NUMBER AND DAMAGE AND MITOCHONDRIAL RNA AND PROTEIN EXPRESSION WILL BE MEASURED. SPACE RADIATION HAS BEEN SHOWN TO INDUCE REACTIVE OXYGEN SPECIES WHICH OXIDATIVELY DAMAGE NUCLEIC ACIDS PROTEINS AND LIPIDS. WE WILL ALSO DETERMINE THE RELATIVE PROTEIN LEVELS AND ACTIVITY OF CRUCIAL MITOCHONDRIAL STRESS RESPONSE PROTEINS WHICH ARE EXPECTED TO MITIGATE CARDIAC INJURY THAT MAY BE CAUSED BY RADIATION-INDUCED OXIDATIVE DAMAGE. THE RESULTS OF THESE EXPERIMENTS WILL FILL KNOWLEDGE GAPS ABOUT RADIATION-INDUCED DEGENERATION OR INJURY TO CARDIAC MITOCHONDRIA AND THE ADAPTIVE STRESS RESPONSE MECHANISMS WHICH POTENTIALLY PROMOTE OR MITIGATE POTENTIAL RISKS TO THE HEART., G7323615720
OpenAlex ID: W4407703315