Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes

Morris, Silke; Molina-Riquelme, Isidora; Barrientos, Gonzalo; Bravo, Francisco; Aedo, Geraldine; Gómez, Wileidy; Lagos, Daniel; Verdejo, Hugo; Peischard, Stefan; Seebohm, Guiscard; Psathaki, Olympia E.; Eisner, Verónica; Busch, Karin B.

doi:10.1016/j.bbabio.2022.148949

Cited by 6 publications

(18 citation statements)

References 100 publications

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“…We observed increased membrane potential measured by TMRE staining and noted a slight increase in CI activity. Hence, our data supports Lima Rosa's observations and our previously reported increase in ROS production [8].…”

Section: Discussionsupporting

confidence: 94%

“…We have recently established a senescence model of induced pluripotent stem cell derived cardiomyocytes and could show that this behaves remarkably similar to a previously established cell model of neonatal rat cardiomyocytes, in which senescence was induced by treatment with doxorubicin [35,36]. Both models exhibit clear markers of cellular senescence, and we observed compromised mitochondrial function as well as ultrastructure, with an increase in truncated and curved cristae [8].…”

Section: Discussionsupporting

confidence: 81%

“…The immobile population, which is thought to be comprised of dimers and higher order oligomers of the ATP Synthase [42], was not affected by doxorubicin treatment. Under consideration of the altered ultrastructure of the IMM in senescent CM with increased number of truncated cristae [8], this may directly restrict movement, reduce maximal step size and thus decrease the diffusion of ATP synthase. This effect is independent of the molecular organisation of ATP synthase.…”

Section: Discussionmentioning

confidence: 99%

“…This implies that cells with high energy demand, such as cardiomyocytes and other muscle cells, contain a large number of mitochondria with a comparatively high cristae density. In a recent study, we established a model of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) in which we induced senescence via mild treatment with doxorubicin [8]. We then compared the said model with primary rat neonatal ventricular cardiomyocytes (NVCM), in which we induced senescence using the same method.…”

Section: Introductionmentioning

confidence: 99%

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Decreased ATP synthase activity is linked to altered spatiotemporal organisation of ATP Synthase in a cellular cardiomyocyte senescent model

Morris,

Schmelter,

Molina-Riquelme

et al. 2024

Preprint

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Heart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. The high energy requirement is reflected in the abundance of mitochondria in cardiomyocytes and the cristae dense architecture of the organelles. The ATP synthase is well known for its involvement in ATP synthesis, but it also plays an important structural role. This is reflected in its spatiotemporal organisation, making single molecule localisation microscopy in living cells a valuable tool to study ATP synthase under different conditions. In the present study, we studied the effects of cellular senescence on the ATP Synthase in cardiomyocytes. We used human induced pluripotent stem cell derived cardiomyocytes as a model system and induced senescence with low doses of doxorubicin. We observed reduced function of the ATP Synthase while membrane potential was increased, indicating a malfunction of the proton sink. These impairments could however not be related to changes in neither expression nor dimerization levels of the complex. Using single-molecule tracking of ATP synthase, we observed stronger confinement of the enzyme in the cristae. This suggests that the altered spatiotemporal organisation of ATP synthase is linked with impaired ATP production in senescent cardiomyocytes.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Decreased ATP synthase activity is linked to altered spatiotemporal organisation of ATP Synthase in a cellular cardiomyocyte senescent model

Morris,

Schmelter,

Molina-Riquelme

et al. 2024

Preprint

Self Cite

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“…It has been reported that Drp1 activation during cardiac IR results in left ventricular dysfunction and that Drp1 inhibition reduces cell death, preserves mitochondrial morphology, and inhibits the mitochondrial permeability transition pore [91,92]. While the relationship between mitochondrial fusion and myocardial senescence has yet to be investigated, elongated mitochondria have been observed in several senescent cell types, including fibroblasts, and are relevant to CVD, iPSC-derived and primary rat cardiomyocytes in vitro [93,94], and the depletion of Fis1 mRNA levels leads to mitochondrial elongation, induces senescence, and increases ROS production [93,95].…”

Section: Mitochondria Dynamics Imbalancementioning

confidence: 99%

Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease

Camacho-Encina,

Booth,

Redgrave

et al. 2024

Cells

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Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disability. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, an increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to an even greater health and economic burden as the global average life expectancy increases and consequently the world’s population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction including energy starvation and oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

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Urolithin A induces cardioprotection and enhanced mitochondrial quality during natural aging and heart failure

Liu,

Faitg,

Tissot

et al. 2023

Preprint

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Cardiovascular diseases remain the primary cause of global mortality, necessitating effective strategies to alleviate their burden. Mitochondrial dysfunction is a driving force behind aging and chronic conditions, including heart disease. Here, we investigate the potential of Urolithin A (UA), a gut microbiome-derived postbiotic that enhances mitophagy, to ameliorate both age-related decline in cardiac function and cardiac failure. We highlight the significance of targeting mitochondria, by comparing gene expression changes in aging human hearts and cardiomyopathies. UA oral administration successfully counteracts mitochondrial and cardiac dysfunctions in preclinical models of aging and heart failure. UA improves both systolic and diastolic heart functions, distinguishing it from other mitochondrial interventions. In cardiomyocytes, UA recovers mitochondrial ultrastructural defects and decline in mitochondrial biomarkers occurring with aging and disease. These findings extend UA?s benefits to heart health, making UA a promising nutritional intervention to evaluate in the clinic to promote healthy cardiovascular function as we age.

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Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes

Cited by 6 publications

References 100 publications

Decreased ATP synthase activity is linked to altered spatiotemporal organisation of ATP Synthase in a cellular cardiomyocyte senescent model

Decreased ATP synthase activity is linked to altered spatiotemporal organisation of ATP Synthase in a cellular cardiomyocyte senescent model

Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease

Urolithin A induces cardioprotection and enhanced mitochondrial quality during natural aging and heart failure

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