The central role of mitochondrial pathology in sepsis-induced cardiomyopathy: from molecular mechanisms to clinical translation

Mitochondrial lipid metabolism dysregulation in sepsis-induced cardiomyopathy: mechanisms and therapeutic strategies

Sepsis-induced cardiomyopathy (SICM) is a common and severe complication of sepsis that contributes substantially to circulatory instability, organ dysfunction, and adverse clinical outcomes. Mitochondrial dysfunction and metabolic reprogramming have emerged as central mechanisms underlying its pathogenesis. Because the adult myocardium depends heavily on mitochondrial lipid metabolism for continuous energy production, disruption of lipid metabolic homeostasis may critically impair myocardial bioenergetics and stress adaptation during sepsis. Current evidence indicates that SICM is accompanied by extensive abnormalities in mitochondrial lipid metabolism, including impaired fatty acid uptake and oxidation, pathological cardiolipin remodeling, excessive lipid peroxidation, ferroptosis, disrupted lipid droplet–mitochondria interactions, and defective mitochondrial dynamics and quality control. These alterations interact with inflammatory signaling, redox imbalance, and metabolism-associated post-translational modifications, collectively promoting adenosine triphosphate (ATP) depletion, lipotoxicity, oxidative injury, and cardiac dysfunction. This review summarizes the physiological organization of mitochondrial lipid metabolism in the healthy myocardium and systematically examines the mechanisms responsible for its dysregulation in SICM. Particular emphasis is placed on cardiolipin remodeling and mitochondrial membrane lipid homeostasis as potential links among impaired substrate oxidation, respiratory chain instability, oxidative stress amplification, and myocardial injury. Emerging therapeutic strategies aimed at restoring metabolic flexibility, preserving mitochondrial membrane integrity, limiting lipid peroxidation, and improving mitochondrial quality control are also evaluated. A better understanding of these mechanisms may support earlier recognition of metabolically distinct SICM phenotypes, improve the timing and selection of targeted interventions, and facilitate the development of more precise approaches to reducing sepsis-related cardiac injury and improving patient outcomes.

Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.

This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming, and critically examines how mitochondria act as signaling hubs for inter-organ crosstalk.

Mitochondrial ncRNAs: From Pathological Regulation to Targeted Therapy in Cardiovascular Diseases

Mitochondrial Integrated Stress Response (mtISR): Mechanistic Basis and Emerging Roles in Skeletal Muscle Pathophysiology

Although mtISR has been characterized in primary mitochondrial myopathies, secondary mitochondrial dysfunction in neuromuscular disorders suggests that mtISR-related pathways may also be activated in these conditions, and its roles in skeletal muscle pathology are discussed.

Mitochondrial dysfunction and the regulatory cell death crosstalk network in chronic obstructive pulmonary disease: from oxidative stress mechanisms to targeted therapeutic strategies

The sustained progression of chronic obstructive pulmonary disease (COPD) may not be independently driven by a single process such as chronic inflammation, oxidative stress, or cell death, but rather originates from a cross-amplification network among “mitochondrial dysfunction-oxidative stress-regulated cell death.” In the context of mitochondrial damage, excessive generation of reactive oxygen species (ROS), damage and release of mitochondrial DNA (mtDNA), and dysregulation of mitochondrial quality control (MQC) collectively promote airway epithelial injury, sustained inflammation, alveolar destruction, and tissue remodeling. Furthermore, regulated cell death modalities such as apoptosis, necroptosis, pyroptosis, and ferroptosis are not isolated from each other but are coupled under a shared context of mitochondrial stress, exhibiting different dominant patterns across various cell types and disease stages. Adopting an integrated perspective encompassing mitochondrial dysfunction, amplified oxidative stress, and the regulated cell death (RCD) cross-network, this article synthesizes current research regarding COPD-related mechanisms, with a focus on mitochondrial damage markers, RCD activity indicators, mechanism-oriented patient stratification, and potential therapeutic strategies targeting mitochondrial homeostasis and cell death pathways. This framework facilitates the transition of COPD understanding from the traditional chronic inflammation model to a more stratified and translationally promising mitochondrial-cell death network model.

Mitochondrial DNA in necrosis-like cell death in failing hearts: evidence and mechanisms fostering damage.

Mitochondrial DNA (mtDNA) is increasingly recognized as a damage-associated molecular pattern (DAMP) that signals mitochondrial injury and the consequent prodeath molecular signature. Such mtDNA release triggers programmed necrotic pathways, specifically necroptosis and pyroptosis, both of which are central to the pathogenesis of heart failure (HF). Mechanically, mtDNA liberated from dysfunctional mitochondria engages cytosolic nucleic acid sensors and that it is associated with activation of necroptotic pathways via the Z-DNA binding protein 1 (ZBP1)-receptor-interacting protein kinase 3 (RIP3)-mixed lineage kinase domain-like pseudokinase (MLKL) axis. Similarly, it can stimulate cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling to promote the de novo synthesis of pro-necroptotic cytokines. Furthermore, the mtDNA release has been shown to promote pyroptosis through nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) and/or absent in melanoma 2 (AIM2) inflammasomes, amplifying a pro-inflammatory environment. The article examines the mechanistic crosstalk between these prodeath, pro-inflammatory pathways with a particular emphasis on how this mechanistic crosstalk drives HF. Consequently, it highlights circulating mtDNA as a key biomarker for HF severity. Lastly, it posits that mtDNA-targeted therapies, such as interventions preserving mitochondrial integrity and limiting mtDNA leakage and oxidation, as well as interventions inhibiting mtDNA-sensing pathways, may offer a viable strategy for novel therapeutic interventions in HF.