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<p>Autophagy is an essential cellular process that maintains homeostasis, regulates organelle turnover, preserves energy balance, and ensures protein quality control. Central to autophagy regulation is calcium (Ca²⁺) signaling, which integrates inputs from multiple Ca²⁺ channels and handling proteins, including L-type and T-type voltage-gated Ca²⁺ channels, transient receptor potential mucolipin (TRPML) channels, inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), the mitochondrial calcium uniporter (MCU), sodium–calcium exchangers (NCX), sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), and calcium/calmodulin-dependent protein kinase II (CaMKII). Although these regulators are well studied, their disease-specific functions remain context-dependent and complex. In cancer, Ca²⁺-regulated autophagy enhances metabolic flexibility, maintains mitochondrial integrity, promotes resistance to chemotherapy, and facilitates immune evasion, thereby supporting tumor growth and survival. Conversely, in cardiovascular diseases (CVDs), autophagy enables cardiomyocytes to adapt to ischemic, inflammatory, and hemodynamic stress. However, dysregulated Ca²⁺ signaling and impaired autophagic flux contribute to tumor progression and pathological cardiac remodeling, respectively. This review explores the molecular mechanisms underlying Ca²⁺-dependent autophagy in cancer and CVDs, providing a detailed analysis of shared signaling pathways and potential therapeutic targets. Discussed in this review, the emerging field of cardio-oncology highlights a mechanistic convergence in which anticancer therapies disrupt cardiomyocyte Ca²⁺ homeostasis, causing mitochondrial Ca²⁺ overload, ER stress, and defective autophagy, ultimately leading to cardiotoxicity, while tumor cells exploit the same pathways to survive therapeutic stress. By elucidating the spatiotemporal dynamics of Ca²⁺ signaling and autophagy, we identify common molecular hubs and propose precision strategies to enhance anticancer efficacy while preserving cardiac function, advancing translational innovation in cardio-oncology.</p> Graphical Abstract <p>Calcium–TRPML–mediated autophagy as a central regulator of cancer progression, cardiovascular homeostasis, and cardio-oncology outcomes. Intracellular Ca²⁺ flux integrates signals from plasma membrane channels (LTCC/TTCC, NCX), endoplasmic reticulum (IP₃R, RyR, SERCA), lysosomes (TRPML1), and mitochondria (MCU) to regulate autophagic flux through CaMKK2–AMPK–mTOR, CaMKII, calcineurin, and TFEB signaling. In cancer, context-dependent Ca²⁺ signaling sustains pro-survival autophagy, metabolic flexibility, and therapy resistance, whereas excessive Ca²⁺ triggers mitochondrial crisis and autophagic cell death. In cardiovascular disease, balanced Ca²⁺-dependent autophagy promotes mitophagy, stress adaptation, and Ca²⁺ homeostasis, while Ca²⁺ overload drives mitochondrial dysfunction, fibrosis, and heart failure. In cardio-oncology, chemotherapy-induced Ca²⁺ dysregulation disrupts lysosomal and mitochondrial function, leading to cardiotoxicity. Precision therapeutic targeting of key Ca²⁺ nodes aims to normalize autophagy and balance anti-cancer efficacy with cardioprotection. Created in BioRender. Kawuribi, V. (2026) <a href="https://BioRender.com/vv9q07d">https://BioRender.com/vv9q07d</a></p> <p></p>

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Calcium and TRPML-Mediated Autophagy: Implications in Cancer, Cardiovascular Diseases, and Cardio-Oncology

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Joseph Adu-Amankwaah,
  • Vincent Kawuribi,
  • Manuella Quaye,
  • Ling Sha,
  • Siwen Fan,
  • Prakriti Kaur,
  • Vishal Sharma,
  • Osinachi Uchechi Okpoko,
  • Zeyuan Yin

摘要

Autophagy is an essential cellular process that maintains homeostasis, regulates organelle turnover, preserves energy balance, and ensures protein quality control. Central to autophagy regulation is calcium (Ca²⁺) signaling, which integrates inputs from multiple Ca²⁺ channels and handling proteins, including L-type and T-type voltage-gated Ca²⁺ channels, transient receptor potential mucolipin (TRPML) channels, inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), the mitochondrial calcium uniporter (MCU), sodium–calcium exchangers (NCX), sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), and calcium/calmodulin-dependent protein kinase II (CaMKII). Although these regulators are well studied, their disease-specific functions remain context-dependent and complex. In cancer, Ca²⁺-regulated autophagy enhances metabolic flexibility, maintains mitochondrial integrity, promotes resistance to chemotherapy, and facilitates immune evasion, thereby supporting tumor growth and survival. Conversely, in cardiovascular diseases (CVDs), autophagy enables cardiomyocytes to adapt to ischemic, inflammatory, and hemodynamic stress. However, dysregulated Ca²⁺ signaling and impaired autophagic flux contribute to tumor progression and pathological cardiac remodeling, respectively. This review explores the molecular mechanisms underlying Ca²⁺-dependent autophagy in cancer and CVDs, providing a detailed analysis of shared signaling pathways and potential therapeutic targets. Discussed in this review, the emerging field of cardio-oncology highlights a mechanistic convergence in which anticancer therapies disrupt cardiomyocyte Ca²⁺ homeostasis, causing mitochondrial Ca²⁺ overload, ER stress, and defective autophagy, ultimately leading to cardiotoxicity, while tumor cells exploit the same pathways to survive therapeutic stress. By elucidating the spatiotemporal dynamics of Ca²⁺ signaling and autophagy, we identify common molecular hubs and propose precision strategies to enhance anticancer efficacy while preserving cardiac function, advancing translational innovation in cardio-oncology.

Graphical Abstract

Calcium–TRPML–mediated autophagy as a central regulator of cancer progression, cardiovascular homeostasis, and cardio-oncology outcomes. Intracellular Ca²⁺ flux integrates signals from plasma membrane channels (LTCC/TTCC, NCX), endoplasmic reticulum (IP₃R, RyR, SERCA), lysosomes (TRPML1), and mitochondria (MCU) to regulate autophagic flux through CaMKK2–AMPK–mTOR, CaMKII, calcineurin, and TFEB signaling. In cancer, context-dependent Ca²⁺ signaling sustains pro-survival autophagy, metabolic flexibility, and therapy resistance, whereas excessive Ca²⁺ triggers mitochondrial crisis and autophagic cell death. In cardiovascular disease, balanced Ca²⁺-dependent autophagy promotes mitophagy, stress adaptation, and Ca²⁺ homeostasis, while Ca²⁺ overload drives mitochondrial dysfunction, fibrosis, and heart failure. In cardio-oncology, chemotherapy-induced Ca²⁺ dysregulation disrupts lysosomal and mitochondrial function, leading to cardiotoxicity. Precision therapeutic targeting of key Ca²⁺ nodes aims to normalize autophagy and balance anti-cancer efficacy with cardioprotection. Created in BioRender. Kawuribi, V. (2026) https://BioRender.com/vv9q07d