A deeper understanding of the functional interaction network among mitochondria, the endoplasmic reticulum, and their associated MAMs is expected to provide a robust theoretical foundation and translational insights for elucidating novel molecular mechanisms underlying lung injury and optimizing therapeutic strategies.
Abstract
The pathogenesis of lung diseases is highly complex and multifactorial, posing a persistent challenge to global public health, while effective therapeutic options remain limited. Therefore, systematically elucidating the cellular and molecular mechanisms underlying lung injury is a crucial prerequisite for developing novel therapeutic strategies. Accumulating evidence highlights that the endoplasmic reticulum and mitochondria are key organelles driving the progression of lung injury. Notably, mitochondria-associated membranes (MAMs) form a structural and functional bridge between the endoplasmic reticulum and mitochondria, highlighting the essential role of inter-organellar communication in maintaining lung function homeostasis. This review comprehensively summarizes the autonomous mechanisms of the mitochondria and endoplasmic reticulum in lung injury-related diseases, with a further focus on the complex architecture and regulatory mechanisms of MAMs. It emphasizes the molecular mechanisms by which dysfunctional MAMs contribute to the onset and progression of lung injury, including Ca²⁺ signaling, oxidative stress, lipid synthesis and transport, UPRER and UPRmt, mitochondrial homeostasis, and cell death. Finally, incorporating recent research advances, we discuss the current challenges and future prospects in this field, with particular emphasis on intervention strategies targeting Ca²⁺ transport at MAMs, mitochondrial quality control, endoplasmic reticulum stress, and metabolic coupling, as well as their potential for clinical translation. Overall, a deeper understanding of the functional interaction network among mitochondria, the endoplasmic reticulum, and their associated MAMs is expected to provide a robust theoretical foundation and translational insights for elucidating novel molecular mechanisms underlying lung injury and optimizing therapeutic strategies.
ABSTRACT Apoptosis is a core program regulating organismal homeostasis and plays a pivotal role in the onset and progression of most diseases. Increasing evidence in recent years indicates that mitochondria are not only central to cellular metabolism but also play a pivotal role in regulating apoptosis. However, no systematic review elucidating how mitochondria finely regulate apoptotic processes through multidimensional mechanisms, including apoptosis‐resistant diseases such as cancer. This paper systematically summarizes the molecular mechanisms by which mitochondria mediate apoptosis. We focus on the regulation of cytochrome c (Cyt c) release by the Bcl‐2 protein family and the activation of downstream caspase cascades. Furthermore, we provide an in‐depth analysis of intrinsic factors, including mitochondrial structural remodeling (membrane rupture, cristae remodeling, and membrane lipid redistribution), dynamics imbalance (fusion, fission, and mitophagy), and mitochondrial DNA abnormalities, as well as extrinsic factors involving interorganelle interactions with the endoplasmic reticulum, lysosomes, and other organelles. Additionally, we review clinical and preclinical advances in drugs targeting these pathways. This review aims to provide a comprehensive perspective on the complex network of mitochondrial regulation of apoptosis and offer valuable insights for developing novel clinical therapeutic strategies for cancer and other diseases.
Rubin Tan, Jinming Zhao, Rong Wang et al.· MedComm· 0 citations
Significance: Intercellular mitochondrial transfer (MT) is increasingly recognized as more than a mechanism of bioenergetic rescue. By modulating mitochondrial quality control, redox homeostasis, immune-cell metabolism, and cell-death susceptibility, MT may influence disease progression and therapeutic response in lung diseases.Recent Advances: Studies have shown that engineered enhancement of mitochondrial biogenesis and transfer can restore mitochondrial homeostasis and attenuate pulmonary fibrosis. In cancer, mitochondrial acquisition can enhance metastatic fitness, redox buffering, and immune escape, whereas directed MT to T cells can improve T-cell antitumor activity. Emerging evidence further links MT to the regulation of oxidative stress, ferroptosis sensitivity, and redox-dependent immune remodeling within the tumor microenvironment.Critical Issues: The biological consequences of MT remain highly context dependent. Transfer efficiency, persistence of transferred mitochondria, cargo quality, and long-term integration into recipient-cell mitochondrial networks remain insufficiently characterized. The same process may promote tissue repair in the injured lung while conferring metabolic advantages on malignant cells, thereby defining important therapeutic and safety boundaries.Future Directions: Future studies should clarify how mitochondrial cargo quality, recipient-cell identity, and microenvironmental state shape MT outcomes. Improved methods for tracking mitochondrial fate and assessing long-term functional integration will be essential for translating MT-based strategies into safe and effective clinical therapies. Antioxid. Redox Signal. 00, 000-000.
Jiwei Zhu, Xuan Lai, W. Lv et al.· Antioxidants and Redox Signa...· 0 citations
This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect, and distinguishes MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types.
Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.
Qian Li, Ming You· Frontiers in Neuroscience· 0 citations
Mitochondria are indispensable organelles that serve as the powerhouses of cells, playing a crucial role in maintaining cellular energy homeostasis. Consequently, mitochondrial dysfunction is recognized as a key pathogenic factor in a wide range of common diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic syndromes and cancers. Due to their multitarget properties and favorable safety profiles, natural products have shown significant potential for regulating key mitochondrial biological processes, including mitobiogenesis, mitophagy, mitochondrial dynamics (fusion and fission), oxidative phosphorylation, and mitochondria-mediated apoptosis. Therefore, they have become an important resource for mitochondria-targeted therapy. Despite significant progress in mechanistic studies in vitro, translating these findings into clinical applications remains a major challenge. This translational gap is primarily due to unfavorable pharmaceutical properties, such as low bioavailability, poor targeted delivery, and rapid metabolic clearance. Additionally, the precise mechanisms governing mitochondria remain to be fully elucidated. In this review, we systematically summarize the specific mitochondrial pathological phenotypes in various diseases and provide a comprehensive overview of natural products that correspond to these phenotypes, along with their mechanisms of action. We also analyze common challenges associated with the absorption, distribution, metabolism, and excretion of these products. By bridging the gap between basic research and clinical application, this review aims to accelerate the development of novel therapeutic strategies for mitochondria-related diseases.
Xinyue Liu, Hu Li, Xuekai Wang et al.· Chinese Journal of Natural M...· 0 citations
Radiation-induced heart disease (RIHD) is a major late complication of thoracic radiotherapy. However, the mechanisms responsible for its long-term progression remain poorly understood. Conventional explanations, such as DNA damage, and oxidative stress, mainly focus on early radiation responses and fail to fully account for the prolonged latency and progressive myocardial remodeling observed in RIHD over years to decades.
This review proposes that persistent disruption of mitochondrial homeostasis represents a central link between early radiation-induced injury and late cardiac remodeling. We systematically summarize the major processes involved in radiation-induced mitochondrial dysfunction. These processes include mtDNA damage, respiratory chain impairment, sustained mitochondrial reactive oxygen species (mitoROS) accumulation, metabolic network remodeling, and defective mitochondrial clearance through mitophagy. We further discuss how acetylation, SUMOylation, and lactylation regulate these processes and contribute to the development and progression of RIHD. Building on this framework, we highlight emerging molecular targets, including NDP52, ATP5F1C, P4HB, and SH3GLB1, as well as the potential protective effects of bioactive compounds derived from traditional Chinese medicine, such as aloe-emodin and astragaloside IV, through restoration of mitochondrial homeostasis. By integrating mitochondrial dysfunction, post-translational modifications, and mitophagy into a unified pathological framework, this review provides new perspectives for early identification and therapeutic intervention in RIHD.
RIHD is not simply an oxidative stress-driven disorder but rather a chronic remodeling process shaped by the interplay among mitochondrial injury, post-translational modifications, and mitophagy dysregulation. This integrated framework links early subcellular alterations to late cardiac remodeling and provides a potential biological explanation for the long latency and progressive nature of RIHD. However, most current evidence is derived from adult models. Future research should specifically address childhood cancer survivors, as radiation exposure during critical periods of cardiac development may result in distinct long-term cardiovascular outcomes.
Na Zuo, Yaling Li, Jun Yang· Frontiers in Pediatrics· 0 citations