Modulation of alveolar macrophage and mitochondrial fitness by medicinal plant-derived nanovesicles to mitigate acute lung injury and viral pneumonia.

Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.

Glutaminolysis regulates endometrial fibrosis in intrauterine adhesion via modulating mitochondrial function.

BACKGROUND: Endometrial fibrosis, a significant characteristic of intrauterine adhesion (IUA), is caused by the excessive differentiation and activation of endometrial stromal cells (ESCs). Glutaminolysis is the metabolic process of glutamine (Gln), which has been implicated in multiple types of organ fibrosis. So far, little is known about whether glutaminolysis plays a role in endometrial fibrosis. METHODS: The activation model of ESCs was constructed by TGF-ß1, followed by RNA-sequencing analysis. Changes in glutaminase1 (GLS1) expression at RNA and protein levels in activated ESCs were verified experimentally. Human IUA samples were collected to verify GLS1 expression in endometrial fibrosis. GLS1 inhibitor and glutamine deprivation were applied to ESCs models to investigate the biological functions and mechanisms of glutaminolysis in ESCs activation. The IUA mice model was established to explore the effect of glutaminolysis inhibition on endometrial fibrosis. RESULTS: We found that GLS1 expression was significantly increased in activated ESCs models and fibrotic endometrium. Glutaminolysis inhibition by GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES or glutamine deprivation treatment suppressed the expression of two fibrotic markers, α-SMA and collagen I, as well as the mitochondrial function and mTORC1 signaling in ESCs. Furthermore, inhibition of the mTORC1 signaling pathway by rapamycin suppressed ESCs activation. In IUA mice models, BPTES treatment significantly ameliorated endometrial fibrosis and improved pregnancy outcomes. CONCLUSION: Glutaminolysis and glutaminolysis-associated mTOR signaling play a role in the activation of ESCs and the pathogenesis of endometrial fibrosis through regulating mitochondrial function. Glutaminolysis inhibition suppresses the activation of ESCs, which might be a novel therapeutic strategy for IUA.

Benzothiazolium-based NIR AIE photosensitizers with type I and II ROS generation for efficient mitochondria-targeted photodynamic therapy.

In this work, a near-infrared emissive photosensitizer of 3,3-dimethyl-N,N-diphenyl-2-(thiophen-2-yl)-3H-indol-6-amine functionlized benzothiazolium (DPITT) was developed. DPITT exhibited aggregation-induced emission effect and potent type I and II reactive oxygen species generation capacities after white light irradiation. Taking advantage of the cationic feature, DPITT penetrated the cell membrane and selectively accumulated in the mitochondria in living cells. Upon white light irradiation, the photosensitized DPITT was able to induce mitochondrial dysfunction, leading to cell death. Photosensitized DPITT was further applied to disrupt the multicellular tumour spheroids, demonstrating its potential application in inhibiting hypoxic solid tumours.

Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.

The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect. AIM: To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death. METHODS: Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts. RESULTS: Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent. CONCLUSION: Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Mitochondrial complex I activity in microglia sustains neuroinflammation.

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.

The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.

A Two-Genome Portrayal of Mitochondrial Disorders: A Review with Clinical Presentations.

Disorders of mitochondrial function are responsible for many inherited neuromuscular and metabolic diseases. Their combination of high mortality, multi-systemic involvement, and economic burden cause devastating effects on patients and their families. Molecular diagnostic tools are becoming increasingly important in providing earlier diagnoses and guiding more precise therapeutic treatments for patients suffering from mitochondrial disorders. This review addresses fundamental molecular concepts relating to the pathogenesis of mitochondrial dysfunction and disorders. A series of short cases highlights the various clinical presentations, inheritance patterns, and pathogenic mutations in nuclear and mitochondrial genes that cause mitochondrial diseases. Graphical and tabular representations of the results are presented to guide the understanding of the important concepts related to mitochondrial molecular genetics and pathology. Emerging technology is incorporating preimplantation genetic testing for mtDNA disorders, while mitochondrial replacement shows promise in significantly decreasing the transfer of diseased mitochondrial DNA (mtDNA) to embryos. Medical professionals must maintain an in-depth understanding of the gene mutations and molecular mechanisms underlying mitochondrial disorders. Continued diagnostic advances and comprehensive management of patients with mitochondrial disorders are essential to achieve robust clinical impacts from comprehensive genomic testing. This is especially true when supported by non-genetic tests such as biochemical analysis, histochemical stains, and imaging studies. Such a multi-pronged investigation should improve the management of mitochondrial disorders by providing accurate and timely diagnoses to reduce disease burden and improve the lives of patients and their families.

Mitochondrial Dysfunction as a Factor of Energy Metabolism Disorders in Type 2 Diabetes Mellitus.

The pathogenesis of type 2 diabetes mellitus (T2DM) is based on the development of insulin resistance, which is a disruption to the ability of the tissues to bind to insulin, leading to a general metabolic disorder. Mitochondria are the main participants in cellular energy metabolism, meaning their dysfunction is associated with the development of insulin resistance in T2DM. Mitochondrial function is affected by insulin resistance in various tissues, including skeletal muscle and the liver, which greatly influence glucose homeostasis throughout the body. This review studies mitochondrial dysfunction in T2DM and its impact on disease progression. In addition, it considers the causes underlying the development of mitochondrial dysfunction in T2DM, including mutations in the mitochondrial genome, mitochondrial DNA methylation, and other epigenetic influences, as well as the impact of impaired mitochondrial membrane potential. New therapeutic strategies for diabetes that have been developed to target the mitochondria will also be presented.

A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.

Mitochondrial stress: a key role of neuroinflammation in stroke.

Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused by the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as a pivotal event contributing to neuronal cell death. The occurrence and progression of neuroinflammation entail intricate processes, prominently featuring mitochondrial dysfunction and adaptive responses. Mitochondria, a double membrane-bound organelle are recognized as the "energy workshop" of the body. Brain is particularly vulnerable to mitochondrial disturbances due to its high energy demands from mitochondria-related energy production. The interplay between mitochondria and neuroinflammation plays a significant role in the pathogenesis of stroke. The biological and pathological consequences resulting from mitochondrial stress have substantial implications for cerebral function. Mitochondrial stress serves as an adaptive mechanism aimed at mitigating the stress induced by the import of misfolded proteins, which occurs in response to stroke. This adaptive response involves a reduction in misfolded protein accumulation and overall protein synthesis. The influence of mitochondrial stress on the pathological state of stroke is underscored by its capacity to interact with neuroinflammation. The impact of mitochondrial stress on neuroinflammation varies according to its severity. Moderate mitochondrial stress can bolster cellular adaptive defenses, enabling cells to better withstand detrimental stressors. In contrast, sustained and excessive mitochondrial stress detrimentally affects cellular and tissue integrity. The relationship between neuroinflammation and mitochondrial stress depends on the degree of mitochondrial stress present. Understanding its role in stroke pathogenesis is instrumental in excavating the novel treatment of stroke. This review aims to provide the evaluation of the cross-talk between mitochondrial stress and neuroinflammation within the context of stroke. We aim to reveal how mitochondrial stress affects neuroinflammation environment in stroke.

Impaired Mitochondrial Function and Marrow Failure in Patients Carrying a Variant of the SRSF4 Gene.

Serine/arginine-rich splicing factors (SRSFs) are a family of proteins involved in RNA metabolism, including pre-mRNA constitutive and alternative splicing. The role of SRSF proteins in regulating mitochondrial activity has already been shown for SRSF6, but SRSF4 altered expression has never been reported as a cause of bone marrow failure. An 8-year-old patient admitted to the hematology unit because of leukopenia, lymphopenia, and neutropenia showed a missense variant of unknown significance of the SRSF4 gene (p.R235W) found via whole genome sequencing analysis and inherited from the mother who suffered from mild leuko-neutropenia. Both patients showed lower SRSF4 protein expression and altered mitochondrial function and energetic metabolism in primary lymphocytes and Epstein-Barr-virus (EBV)-immortalized lymphoblasts compared to healthy donor (HD) cells, which appeared associated with low mTOR phosphorylation and an imbalance in the proteins regulating mitochondrial biogenesis (i.e., CLUH) and dynamics (i.e., DRP1 and OPA1). Transfection with the wtSRSF4 gene restored mitochondrial function. In conclusion, this study shows that the described variant of the SRSF4 gene is pathogenetic and causes reduced SRSF4 protein expression, which leads to mitochondrial dysfunction. Since mitochondrial function is crucial for hematopoietic stem cell maintenance and some genetic bone marrow failure syndromes display mitochondrial defects, the SRSF4 mutation could have substantially contributed to the clinical phenotype of our patient.

Mitochondrial dysfunction and therapeutic perspectives in osteoporosis.

Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass and structural deterioration of bone tissue, resulting in heightened vulnerability to fractures due to increased bone fragility. This condition primarily arises from an imbalance between the processes of bone resorption and formation. Mitochondrial dysfunction has been reported to potentially constitute one of the most crucial mechanisms influencing the pathogenesis of osteoporosis. In essence, mitochondria play a crucial role in maintaining the delicate equilibrium between bone formation and resorption, thereby ensuring optimal skeletal health. Nevertheless, disruption of this delicate balance can arise as a consequence of mitochondrial dysfunction. In dysfunctional mitochondria, the mitochondrial electron transport chain (ETC) becomes uncoupled, resulting in reduced ATP synthesis and increased generation of reactive oxygen species (ROS). Reinforcement of mitochondrial dysfunction is further exacerbated by the accumulation of aberrant mitochondria. In this review, we investigated and analyzed the correlation between mitochondrial dysfunction, encompassing mitochondrial DNA (mtDNA) alterations, oxidative phosphorylation (OXPHOS) impairment, mitophagy dysregulation, defects in mitochondrial biogenesis and dynamics, as well as excessive ROS accumulation, with regards to OP (Figure 1). Furthermore, we explore prospective strategies currently available for modulating mitochondria to ameliorate osteoporosis. Undoubtedly, certain therapeutic strategies still require further investigation to ensure their safety and efficacy as clinical treatments. However, from a mitochondrial perspective, the potential for establishing effective and safe therapeutic approaches for osteoporosis appears promising.

Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.

Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.

Traumatic Brain Injury Alters the Trajectory of Age-Related Mitochondrial Change.

Background: Some epidemiologic studies associate traumatic brain injury (TBI) with Alzheimer's disease (AD). Objective: To test whether a TBI-induced acceleration of age-related mitochondrial change could potentially mediate the reported TBI-AD association. Methods: We administered unilateral controlled cortical impact (CCI) or sham injuries to 5-month-old C57BL/6J and tau transgenic rTg4510 mice. In the non-transgenics, we assessed behavior (1-5 days, 1 month, and 15 months), lesion size (1 and 15 months), respiratory chain enzymes (1 and 15 months), and mitochondrial DNA copy number (mtDNAcn) (1 and 15 months) after CCI/sham. In the transgenics we quantified post-injury mtDNAcn and tangle burden. Results: In the non-transgenics CCI caused acute behavioral deficits that improved or resolved by 1-month post-injury. Protein-normalized complex I and cytochrome oxidase activities were not significantly altered at 1 or 15 months, although complex I activity in the CCI ipsilesional cortex declined during that period. Hippocampal mtDNAcn was not altered by injury at 1 month, increased with age, and rose to the greatest extent in the CCI contralesional hippocampus. In the injured then aged transgenics, the ipsilesional hippocampus contained less mtDNA and fewer tangles than the contralesional hippocampus; mtDNAcn and tangle counts did not correlate. Conclusions: As mice age their brains increase mtDNAcn as part of a compensatory response that preserves mitochondrial function, and TBI enhances this response. TBI may, therefore, increase the amount of compensation required to preserve late-life mitochondrial function. If TBI does modify AD risk, altering the trajectory or biology of aging-related mitochondrial changes could mediate the effect.

Age-Related Macular Degeneration and Mitochondria-Associated Autoantibodies: A Review of the Specific Pathogenesis and Therapeutic Strategies.

Age-related macular degeneration (AMD) is a severe retinal disease that causes irreversible visual loss and blindness in elderly populations worldwide. The pathological mechanism of AMD is complex, involving the interactions of multiple environmental and genetic factors. A poor understanding of the disease leads to limited treatment options and few effective prevention methods. The discovery of autoantibodies in AMD patients provides an opportunity to explore the pathogenesis and treatment direction of the disease. This review focuses on the mitochondria-associated autoantibodies and summarizes the functional roles of mitochondria under physiological conditions and their alterations during the pathological states. Additionally, it discusses the crosstalk between mitochondria and other organelles, as well as the mitochondria-related therapeutic strategies in AMD.

An integral role of mitochondrial function in the pathophysiology of preeclampsia.

Preeclampsia (PE) is associated with high maternal and perinatal morbidity and mortality. The development of effective treatment strategies remains a major challenge due to the limited understanding of the pathogenesis. In this review, we summarize the current understanding of PE research, focusing on the molecular basis of mitochondrial function in normal and PE placentas, and discuss perspectives on future research directions. Mitochondria integrate numerous physiological processes such as energy production, cellular redox homeostasis, mitochondrial dynamics, and mitophagy, a selective autophagic clearance of damaged or dysfunctional mitochondria. Normal placental mitochondria have evolved innovative survival strategies to cope with uncertain environments (e.g., hypoxia and nutrient starvation). Cytotrophoblasts, extravillous trophoblast cells, and syncytiotrophoblasts all have distinct mitochondrial morphology and function. Recent advances in molecular studies on the spatial and temporal changes in normal mitochondrial function are providing valuable insight into PE pathogenesis. In PE placentas, hypoxia-mediated mitochondrial fission may induce activation of mitophagy machinery, leading to increased mitochondrial fragmentation and placental tissue damage over time. Repair mechanisms in mitochondrial function restore placental function, but disruption of compensatory mechanisms can induce apoptotic death of trophoblast cells. Additionally, molecular markers associated with repair or compensatory mechanisms that may influence the development and progression of PE are beginning to be identified. However, contradictory results have been obtained regarding some of the molecules that control mitochondrial biogenesis, dynamics, and mitophagy in PE placentas. In conclusion, understanding how the mitochondrial morphology and function influence cell fate decisions of trophoblast cells is an important issue in normal as well as pathological placentation biology. Research focusing on mitochondrial function will become increasingly important for elucidating the pathogenesis and effective treatment strategies of PE.

Stress response silencing by an E3 ligase mutated in neurodegeneration.

Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.

Mitochondrial transfer and implications for muscle function in idiopathic inflammatory myopathies.

Impairment in cellular bioenergetics as either the cause, consequence, or major contributor of tissue damage has drawn increasing scientific curiosity across aging and chronic health conditions, with mitochondrial dysfunction emerging as a central mechanism in the pathogenesis of a variety of inflammatory and degenerative disorders. Beyond bioenergetics, mitochondria play critical regulatory roles in programmed cell death of dysfunctional/defective cells as well as in metabolite synthesis and metabolic signalling. Further, extra-cellular exposure to fragmentation of injured mitochondria is associated with incitement of systemic and organ-based inflammation. Thus, mitochondrial function has recently drawn intense, spectral scientific interest as an integral component across maladies.In muscle, mitochondrial dysfunction is clinically associated with atrophy and diminished endurance. Direct myo-histopathological evidence characterising loss of mitochondrial integrity as a hallmark of muscle compromise was first noticed in inclusion body myositis (IBM). This was followed by the discovery of multiple deletions in mitochondrial DNA in sarcopenia, IBM, and other inflammatory myopathies, like dermatomyositis. Though fraught with bioethical considerations, the transplant technology of mitochondrial transfer is swiftly gaining prominence in cellular biology and muscle physiology to remediate mitochondrial diminution and dysfunction. Assembling seminal works and recent developments, this review ventures into the rapidly evolving landscape of mitochondrial transfer, focusing on its implications on muscle function, and offers an integrated perspective on the potential roles of mitochondrial transfer and its implications for preserving and restoring muscle health. Presented here is a consolidated viewpoint on mitochondrial transfer in idiopathic inflammatory myopathies.