bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–05–19
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. AMPK as a mediator of tissue preservation: time for a shift in dogma?
  2. Mitochondrial heterogeneity and adaptations to cellular needs.
  3. AMPK activation eliminates senescent cells in diabetic wound by inducing NCOA4 mediated ferritinophagy.
  4. Aging-Related Sarcopenia: Metabolic Characteristics and Therapeutic Strategies.
  5. Sarcopenia: a dive into metabolism to promote a multimodal, preventive, and regenerative approach.
  6. MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
  7. Ketogenic diet induces p53-dependent cellular senescence in multiple organs.
  8. Bacteria-organelle communication in physiology and disease.
  9. Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases.
  10. The clinical significance of mitochondrial calcium uniporter in gastric cancer patients and its preliminary exploration of the impact on mitochondrial function and metabolism.
  1. Nat Rev Endocrinol. 2024 May 17.
    AMPK as a mediator of tissue preservation: time for a shift in dogma?
    Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.
      Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.
    DOI:  https://doi.org/10.1038/s41574-024-00992-y
  2. Nat Cell Biol. 2024 May;26(5): 674-686
    Mitochondrial heterogeneity and adaptations to cellular needs.
    Melia Granath-Panelo, Shingo Kajimura.
      Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.
    DOI:  https://doi.org/10.1038/s41556-024-01410-1
  3. Mol Med. 2024 May 17. 30(1): 63
    AMPK activation eliminates senescent cells in diabetic wound by inducing NCOA4 mediated ferritinophagy.
    Mengqian Liu, Xuerong Wei, Zijun Zheng, Erlian Xie, Qiuyi Yu, Yanbin Gao, Jun Ma, Lei Yang.
       BACKGROUND: Diabetic wounds are one of the long-term complications of diabetes, with a disordered microenvironment, diabetic wounds can easily develop into chronic non-healing wounds, which can impose a significant burden on healthcare. In diabetic condition, senescent cells accumulate in the wound area and suppress the wound healing process. AMPK, as a molecule related to metabolism, has a close relationship with aging and diabetes. The purpose of this study was to investigate the effects of AMPK activation on wound healing and explore the underlying mechanisms.
    METHODS: AMPK activator A769662 was topically applied in wound models of diabetic mice. Alterations in the wound site were observed and analyzed by immunohistochemistry. The markers related to autophagy and ferritinophagy were analyzed by western blotting and immunofluorescence staining. The role of AMPK activation and ferritinophagy were also analyzed by western blotting.
    RESULTS: Our results show that AMPK activation improved diabetic wound healing and reduced the accumulation of senescent cells. Intriguingly, we found that AMPK activation-induced ferroptosis is autophagy-dependent. We detected that the level of ferritin had deceased and NCOA4 was markedly increased after AMPK activation treatment. We further investigated that NCOA4-mediated ferritinophagy was involved in ferroptosis triggered by AMPK activation. Most importantly, AMPK activation can reverse the ferroptosis-insensitive of senescent fibroblast cells in diabetic mice wound area and promote wound healing.
    CONCLUSIONS: These results suggest that activating AMPK can promote diabetic wound healing by reversing the ferroptosis-insensitive of senescent fibroblast cells. AMPK may serve as a regulatory factor in senescent cells in the diabetic wound area, therefore AMPK activation can become a promising therapeutic method for diabetic non-healing wounds.
    Keywords:  AMPK; Autophagy; Cellular senescence; Diabetic wound; Ferroptosis
    DOI:  https://doi.org/10.1186/s10020-024-00825-8
  4. Aging Dis. 2024 Apr 19.
    Aging-Related Sarcopenia: Metabolic Characteristics and Therapeutic Strategies.
    Yonglian Chen, Jinhui Wu.
      The proportion of the elderly population is gradually increasing as a result of medical care advances, leading to a subsequent surge in geriatric diseases that significantly impact quality of life and pose a substantial healthcare burden. Sarcopenia, characterized by age-related decline in skeletal muscle mass and quality, affects a considerable portion of older adults, particularly the elderly, and can result in adverse outcomes such as frailty, fractures, bedridden, hospitalization, and even mortality. Skeletal muscle aging is accompanied by underlying metabolic changes. Therefore, elucidating these metabolic profiles and specific mechanisms holds promise for informing prevention and treatment strategies for sarcopenia. This review provides a comprehensive overview of the key metabolites identified in current clinical studies on sarcopenia and their potential pathophysiological alterations in metabolic activity. Besides, we examine potential therapeutic strategies for sarcopenia from a perspective focused on metabolic regulation.
    DOI:  https://doi.org/10.14336/AD.2024.0407
  5. Mech Ageing Dev. 2024 May 13. pii: S0047-6374(24)00041-1. [Epub ahead of print] 111941
    Sarcopenia: a dive into metabolism to promote a multimodal, preventive, and regenerative approach.
    Virginia Boccardi.
      Sarcopenia, the age-related loss of skeletal muscle mass and function, poses a significant challenge in the field of gerontology, impacting the health and independence of older adults. By synthesizing current research findings and theoretical frameworks, this perspective elucidates the multifaceted mechanisms underlying sarcopenia, mainly focusing on energy balance and metabolic processes. Furthermore, the manuscript explores the implications of sarcopenia on overall health outcomes, functional decline, and quality of life in older individuals.
    Keywords:  Frailty; aging; metabolism; sarcopenia
    DOI:  https://doi.org/10.1016/j.mad.2024.111941
  6. Circ Res. 2024 May 15.
    MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
    Barbara Roman, Yusuf Mastoor, Junhui Sun, Hector Chapoy Villanueva, Gabriela Hinojosa, Danielle Springer, Julia C Liu, Elizabeth Murphy.
       BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.
    METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.
    RESULTS: Knock out MICU3 hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, overexpression of MICU3 hearts exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, overexpression of MICU3 animals exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in overexpression of MICU3 hearts compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.
    CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.
    Keywords:  calcium; cardiomegaly; echocardiography; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324026
  7. Sci Adv. 2024 May 17. 10(20): eado1463
    Ketogenic diet induces p53-dependent cellular senescence in multiple organs.
    Sung-Jen Wei, Joseph R Schell, E Sandra Chocron, Mahboubeh Varmazyad, Guogang Xu, Wan Hsi Chen, Gloria M Martinez, Felix F Dong, Prethish Sreenivas, Rolando Trevino, Haiyan Jiang, Yan Du, Afaf Saliba, Wei Qian, Brandon Lorenzana, Alia Nazarullah, Jenny Chang, Kumar Sharma, Erin Munkácsy, Nobuo Horikoshi, David Gius.
      A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for weight loss, detrimental effects have also been reported. Here, we show mice on two different KDs and, at different ages, induce cellular senescence in multiple organs, including the heart and kidney. This effect is mediated through adenosine monophosphate-activated protein kinase (AMPK) and inactivation of mouse double minute 2 (MDM2) by caspase-2, leading to p53 accumulation and p21 induction. This was established using p53 and caspase-2 knockout mice and inhibitors to AMPK, p21, and caspase-2. In addition, senescence-associated secretory phenotype biomarkers were elevated in serum from mice on a KD and in plasma samples from patients on a KD clinical trial. Cellular senescence was eliminated by a senolytic and prevented by an intermittent KD. These results have important clinical implications, suggesting that the effects of a KD are contextual and likely require individual optimization.
    DOI:  https://doi.org/10.1126/sciadv.ado1463
  8. J Cell Biol. 2024 Jul 01. pii: e202310134. [Epub ahead of print]223(7):
    Bacteria-organelle communication in physiology and disease.
    Yi-Tang Lee, Mumine Senturk, Youchen Guan, Meng C Wang.
      Bacteria, omnipresent in our environment and coexisting within our body, exert dual beneficial and pathogenic influences. These microorganisms engage in intricate interactions with the human body, impacting both human health and disease. Simultaneously, certain organelles within our cells share an evolutionary relationship with bacteria, particularly mitochondria, best known for their energy production role and their dynamic interaction with each other and other organelles. In recent years, communication between bacteria and mitochondria has emerged as a new mechanism for regulating the host's physiology and pathology. In this review, we delve into the dynamic communications between bacteria and host mitochondria, shedding light on their collaborative regulation of host immune response, metabolism, aging, and longevity. Additionally, we discuss bacterial interactions with other organelles, including chloroplasts, lysosomes, and the endoplasmic reticulum (ER).
    DOI:  https://doi.org/10.1083/jcb.202310134
  9. Biochem Pharmacol. 2024 May 11. pii: S0006-2952(24)00261-2. [Epub ahead of print]225 116278
    Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases.
    Wen-Di Ge, Tian-Tian Du, Cao-Yang Wang, Lu-Ning Sun, Yong-Qing Wang.
      Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.
    Keywords:  Calcium; Endoplasmic Reticulum; Kidney Diseases; Mitochondria; Mitochondrial Associated Membranes
    DOI:  https://doi.org/10.1016/j.bcp.2024.116278
  10. Front Oncol. 2024 ;14 1355559
    The clinical significance of mitochondrial calcium uniporter in gastric cancer patients and its preliminary exploration of the impact on mitochondrial function and metabolism.
    Zipeng Xu, Xia Chen, Haicun Zhou, Luming Sun, Ruobing Bai, Wenwen Yu, Junhao Yang, Hongbin Liu.
       Objective: The objective of this study is to elucidate the influence of MCU on the clinical pathological features of GC patients, to investigate the function and mechanism of the mitochondrial calcium uptake transporter MCU in the initiation and progression of GC, and to explore its impact on the metabolic pathways and biosynthesis of mitochondria. The ultimate goal is to identify novel targets and strategies for the clinical management of GC patients.
    Methods: Tumor and adjacent tissue specimens were obtained from 205 patients with gastric cancer, and immunohistochemical tests were performed to assess the expression of MCU and its correlation with clinical pathological characteristics and prognosis. Data from TCGA, GTEx and GEO databases were retrieved for gastric cancer patients, and bioinformatics analysis was utilized to investigate the association between MCU expression and clinical pathological features. Furthermore, we conducted an in-depth analysis of the role of MCU in GC patients. We investigated the correlation between MCU expression in GC and its impact on mitochondrial function, metabolism, biosynthesis, and immune cells. Additionally, we studied the proteins or molecules that interact with MCU.
    Results: Our research revealed high expression of MCU in the GC tissues. This high expression was associated with poorer T and N staging, and indicated a worse disease-free survival period. MCU expression was positively correlated with mitochondrial function, mitochondrial metabolism, nucleotide, amino acid, and fatty acid synthesis metabolism, and negatively correlated with nicotinate and nicotinamide metabolism. Furthermore, the MCU also regulates the function of the mitochondrial oxidative respiratory chain. The MCU influences the immune cells of GC patients and regulates ROS generation, cell proliferation, apoptosis, and resistance to platinum-based drugs in gastric cancer cells.
    Conclusion: High expression of MCU in GC indicates poorer clinical outcomes. The expression of the MCU are affected through impacts the function of mitochondria, energy metabolism, and cellular biosynthesis in gastric cancer cells, thereby influencing the growth and metastasis of gastric cancer cells. Therefore, the mitochondrial changes regulated by MCU could be a new focus for research and treatment of GC.
    Keywords:  biosynthesis; gastric cancer; metabolism; mitochondrial; mitochondrial calcium uniporter
    DOI:  https://doi.org/10.3389/fonc.2024.1355559
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