Intercellular Mitochondria Transfer in Lung Diseases: New Mechanisms, Risks, Therapeutic Boundaries.

Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.

Mitochondrial transfer has emerged as a previously underappreciated layer of intercellular communication within the tumor microenvironment. Accumulating evidence demonstrates its contribution to the metabolic and functional plasticity of both tumor and immune cells. Rather than representing a rare stochastic event, mitochondrial exchange occurs across multiple cell types-including cancer cells, stromal cells, and infiltrating immune cells-via distinct structures such as tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and transient cell fusion events. In tumor cells, acquisition of exogenous mitochondria is commonly associated with enhanced oxidative phosphorylation (OXPHOS), improved metabolic adaptation, and increased tolerance to therapeutic stress. Conversely, immune cells that undergo mitochondrial depletion or receive dysfunctional mitochondria frequently display impaired bioenergetic capacity and diminished effector function, thereby contributing to immune dysfunction in the TME. Recent advances in intravital imaging, single-cell technologies, and lineage tracing have provided compelling evidence that mitochondrial transfer is a dynamic, context-dependent and often directional process. Beyond metabolic effects, mitochondrial components, particularly mitochondrial DNA (mtDNA), can engage innate immune pathways including TLR9, NLRP3, and cGAS-STING, thus modulating inflammatory signaling and antitumor immunity. Overall, mitochondrial transfer functions as a bidirectional regulator of immunometabolic states in cancer, with potential either to support tumor progression or to modulate immune responses, depending on cellular context. Understanding the molecular determinants governing this process may offer opportunities to selectively target pathological mitochondrial exchange or to exploit it for therapeutic benefit in cancer immunotherapy. This comprehensive review examines the molecular mechanisms, immunological consequences, and therapeutic implications of mitochondrial transfer in cancer.

The Role of Mitochondrial ROS in Neoplastic Transformations, Progression and Therapeutic Targeting

Mitochondria are central regulators of cellular metabolism and survival and play a pivotal role in cancer development and progression through the production of reactive oxygen species (ROS), control of calcium homeostasis, regulation of autophagy, and modulation of cell death pathways. Mitochondria-derived ROS (mtROS) act as signaling mediators that influence tumor initiation, proliferation, metabolic reprogramming, metastasis, and therapeutic resistance by altering redox homeostasis, damaging mitochondrial DNA, and reshaping the tumor microenvironment. In addition to meeting the bioenergetic and biosynthetic requirements of rapidly proliferating cancer cells, mitochondrial metabolism modulates immune responses and supports cancer cell adaptation to hypoxia and nutrient deprivation. Accumulating evidence also highlights the dual role of mtROS, which can promote tumor progression at moderate levels yet trigger oxidative stress-induced cell death when excessively increased, making mitochondrial redox signaling an attractive therapeutic target. This review summarizes the major sources and regulation of mtROS, their involvement in cancer-associated signaling pathways, mitochondrial calcium dynamics, metabolic adaptations, and resistance to anticancer therapies, and discusses current and emerging mitochondrial-targeted strategies aimed at exploiting mtROS signaling to improve cancer treatment outcomes.

Platelet-derived mitochondrial transfer in cancer metastasis: mechanisms, functional consequences, and translational opportunities

Mitochondrial Fitness as a Functional Immune Checkpoint in Cancer: Metabolic Plasticity, Tumor Evolution, and Immunotherapy

Mitochondria are increasingly recognized as dynamic regulators of cancer-cell adaptation, immune function, and therapeutic response. Beyond their canonical role in energy production, mitochondrial metabolism, dynamics, quality control, and stress signaling influence tumor-cell survival and the capacity of immune effector cells to sustain antitumor activity within the tumor microenvironment. In this narrative review, we examine mitochondrial fitness as a multidimensional functional property encompassing bioenergetic capacity, metabolic flexibility, redox homeostasis, mitochondrial quality control, and adaptation to cellular and therapeutic stress. We propose the mitochondrial functional immune checkpoint as a conceptual framework linking mitochondrial fitness in malignant and immune cells to tumor–immune interactions and immunotherapy response. We discuss how mitochondrial metabolic plasticity, mitochondrial stress and mtDNA signaling, reactive oxygen species, mitochondrial dynamics, and intercellular mitochondrial transfer contribute to immune escape and treatment resistance. We further examine the relevance of mitochondrial fitness to immune checkpoint blockade, CAR-T-cell therapy, and T-cell-redirecting bispecific antibodies, with particular attention to hematological malignancies, including acute myeloid leukemia and multiple myeloma, while incorporating selected evidence from solid tumors to highlight shared mitochondrial mechanisms and their broader oncologic relevance. Finally, we discuss emerging strategies for mitochondrial targeting and functional mitochondrial profiling and their potential integration with established molecular and measurable residual disease assessments. Current evidence supports mitochondrial biology as a complementary dimension of precision oncology, although important challenges remain regarding context dependence, biomarker standardization, therapeutic selectivity, and preservation of immune-cell fitness. Prospective studies are needed to determine whether functional mitochondrial profiling can improve patient stratification and guide rational therapeutic combinations that selectively exploit tumor mitochondrial vulnerabilities while preserving effective antitumor immunity.

Mitochondrial transplantation for cardiovascular diseases: opportunities and challenges—a review

Mitochondria serve as central hubs for cellular energy production, calcium homeostasis, and signal transduction, playing pivotal roles in maintaining cardiomyocyte viability and function. Mitochondrial dysfunction is closely implicated in the pathogenesis of various cardiovascular diseases, including myocardial ischemia-reperfusion injury, myocardial infarction, doxorubicin-induced cardiomyopathy, peripheral artery disease, and diabetic cardiomyopathy. Mitochondrial transplantation (MT) has emerged as a promising therapeutic strategy that involves delivering functional exogenous mitochondria to damaged tissues to restore bioenergetic capacity and promote cellular repair mechanisms. Preclinical studies across multiple animal models have demonstrated its efficacy in reducing infarct size, enhancing functional recovery, and modulating inflammatory responses. Current MT techniques encompass diverse approaches for mitochondrial isolation, storage, and delivery, with both direct injection and indirect transplantation methods under investigation. Despite encouraging results from early-phase clinical trials highlighting its safety and feasibility, significant translational challenges remain. These include unresolved mechanistic debates—such as whether benefits arise from direct mitochondrial integration or paracrine immunomodulation—as well as issues related to long-term safety, standardization of mitochondrial preparations, optimization of delivery routes, and the need for rigorous, large-scale randomized controlled trials. This review summarizes the current evidence, critically examines the opportunities and barriers in the field, and outlines key directions for future research to advance MT toward clinical application in cardiovascular medicine.

Mitochondrial Dysfunction in Renal Cell Carcinoma: A Comprehensive Review of Pathogenic Mechanisms and Emerging Therapeutic Opportunities

In renal cell carcinoma (RCC), alterations in cellular metabolism are a defining feature, among which impaired mitochondrial function stands out as a key factor influencing both tumor aggressiveness and patient responses to therapy. The aim of this review is to systematically synthesize current knowledge on the role of mitochondrial dysfunction in RCC pathogenesis and to explore emerging therapeutic strategies targeting mitochondrial vulnerabilities. This comprehensive analysis examines the integrated dysregulation of core mitochondrial processes—bioenergetic metabolism, organelle dynamics, programmed cell death pathways, redox homeostasis, and selective autophagy—in driving RCC pathogenesis. Our synthesis reveals how genetic drivers, molecular regulators, and microenvironmental cues converge to remodel mitochondrial function, creating both adaptive advantages and therapeutic vulnerabilities. A paradoxical duality emerges in mitochondrial biology: processes such as fission, mitophagy, and reactive oxygen species (ROS) generation can simultaneously support tumor adaptation while rendering cells susceptible to targeted interventions. We evaluate emerging therapeutic approaches directed at mitochondrial vulnerabilities, including metabolic inhibitors, nanoscale delivery systems, and phytochemical agents, while addressing current limitations in specificity and resistance mechanisms. Based on current preclinical evidence, this integrated perspective establishes mitochondrial dysfunction as a central determinant of RCC malignancy and suggests potential combinatorial strategies for precision oncology approaches that warrant further investigation.