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Annals of Surgery Dec 2023To test whether mitochondrial transplantation (MITO) mitigates damage in 2 models of acute kidney injury (AKI).
OBJECTIVES
To test whether mitochondrial transplantation (MITO) mitigates damage in 2 models of acute kidney injury (AKI).
BACKGROUND
MITO is a process where exogenous isolated mitochondria are taken up by cells. As virtually any morbid clinical condition is characterized by mitochondrial distress, MITO may find a role as a treatment modality in numerous clinical scenarios including AKI.
METHODS
For the in vitro experiments, human proximal tubular cells were damaged and then treated with mitochondria or placebo. For the ex vivo experiments, we developed a non-survival ex vivo porcine model mimicking the donation after cardiac death renal transplantation scenario. One kidney was treated with mitochondria, although the mate organ received placebo, before being perfused at room temperature for 24 hours. Perfusate samples were collected at different time points and analyzed with Raman spectroscopy. Biopsies taken at baseline and 24 hours were analyzed with standard pathology, immunohistochemistry, and RNA sequencing analysis.
RESULTS
In vitro, cells treated with MITO showed higher proliferative capacity and adenosine 5'-triphosphate production, preservation of physiological polarization of the organelles and lower toxicity and reactive oxygen species production. Ex vivo, kidneys treated with MITO shed fewer molecular species, indicating stability. In these kidneys, pathology showed less damage whereas RNAseq analysis showed modulation of genes and pathways most consistent with mitochondrial biogenesis and energy metabolism and downregulation of genes involved in neutrophil recruitment, including IL1A, CXCL8, and PIK3R1.
CONCLUSIONS
MITO mitigates AKI both in vitro and ex vivo.
Topics: Humans; Swine; Animals; Kidney Transplantation; Reperfusion Injury; Kidney; Mitochondria; Acute Kidney Injury
PubMed: 37450698
DOI: 10.1097/SLA.0000000000006005 -
Viruses Dec 2023Mitochondria have been identified as the "powerhouse" of the cell, generating the cellular energy, ATP, for almost seven decades. Research over time has uncovered a... (Review)
Review
Mitochondria have been identified as the "powerhouse" of the cell, generating the cellular energy, ATP, for almost seven decades. Research over time has uncovered a multifaceted role of the mitochondrion in processes such as cellular stress signaling, generating precursor molecules, immune response, and apoptosis to name a few. Dysfunctional mitochondria resulting from a departure in homeostasis results in cellular degeneration. Viruses hijack host cell machinery to facilitate their own replication in the absence of a bonafide replication machinery. Replication being an energy intensive process necessitates regulation of the host cell oxidative phosphorylation occurring at the electron transport chain in the mitochondria to generate energy. Mitochondria, therefore, can be an attractive therapeutic target by limiting energy for viral replication. In this review we focus on the physiology of oxidative phosphorylation and on the limited studies highlighting the regulatory effects viruses induce on the electron transport chain.
Topics: Humans; Oxidative Phosphorylation; Mitochondria; Apoptosis; Signal Transduction; Virus Diseases; Phosphorylation; Oxidative Stress
PubMed: 38140621
DOI: 10.3390/v15122380 -
Free Radical Biology & Medicine Nov 2023Ferroptosis is a type of oxidative cell death that can occur in neurodegenerative diseases and involves damage to mitochondria. Previous studies demonstrated that...
Ferroptosis is a type of oxidative cell death that can occur in neurodegenerative diseases and involves damage to mitochondria. Previous studies demonstrated that preventing mitochondrial dysfunction can rescue cells from ferroptotic cell death. However, the complexity of mitochondrial dysfunction and the timing of therapeutic interventions make it difficult to develop an effective treatment strategy against ferroptosis in neurodegeneration conditions. In this study, we explored the use of mitochondrial transplantation as a novel therapeutic approach for preventing ferroptotic neuronal cell death. Our data showed that isolated exogenous mitochondria were incorporated into both healthy and ferroptotic immortalized hippocampal HT-22 cells and primary cortical neurons (PCN). The mitochondrial incorporation was accompanied by increased metabolic activity and cell survival through attenuating lipid peroxidation and mitochondrial superoxide production. Further, the function of mitochondrial complexes I, III and V activities contributed to the neuroprotective activity of exogenous mitochondria. Similarly, we have also showed the internalization of exogenous mitochondria in mouse PCN; these internalized mitochondria were found to effectively preserve the neuronal networks when challenged with ferroptotic stimuli. The administration of exogenous mitochondria into the axonal compartment of a two-compartment microfluidic device induced mitochondrial transportation to the cell body, which prevented fragmentation of the neuronal network in ferroptotic PCN. These findings suggest that mitochondria transplantation may be a promising therapeutic approach for protecting neuronal cells from ferroptotic cell death.
Topics: Mice; Animals; Ferroptosis; Cell Death; Mitochondria; Neurons; Cell Line
PubMed: 37536459
DOI: 10.1016/j.freeradbiomed.2023.07.034 -
Human Molecular Genetics May 2024
Topics: Humans; Mitochondrial Diseases; DNA, Mitochondrial; Mitochondria
PubMed: 38779767
DOI: 10.1093/hmg/ddae049 -
Aging Cell Oct 2023Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several...
Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere-driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere-binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction-induced senescence, which may facilitate continued cellular functions.
Topics: Telomere; Telomere-Binding Proteins; Mitochondria; Cellular Senescence; Fibroblasts
PubMed: 37688329
DOI: 10.1111/acel.13941 -
Mitochondrion May 2024Mitochondria are an indispensable part of the cell that plays a crucial role in regulating various signaling pathways, energy metabolism, cell differentiation,... (Review)
Review
Mitochondria are an indispensable part of the cell that plays a crucial role in regulating various signaling pathways, energy metabolism, cell differentiation, proliferation, and cell death. Since mitochondria have their own genetic material, they differ from their nuclear counterparts, and dysregulation is responsible for a broad spectrum of diseases. Mitochondrial dysfunction is associated with several disorders, including neuro-muscular disorders, cancer, and premature aging, among others. The intricacy of the field is due to the cross-talk between nuclear and mitochondrial genes, which has also improved our knowledge of mitochondrial functions and their pathogenesis. Therefore, interdisciplinary research and communication are crucial for mitochondrial biology and medicine due to the challenges they pose for diagnosis and treatment. The ninth annual conference of the Society for Mitochondria Research and Medicine (SMRM)- India, titled "Mitochondria in Biology and Medicine" was organized at the Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India, on June 21-23, 2023. The latest advancements in the field of mitochondrial biology and medicine were discussed at the conference. In this article, we summarize the entire event for the benefit of researchers working in the field of mitochondrial biology and medicine.
Topics: Humans; Mitochondria; Mitochondrial Diseases; Animals; India
PubMed: 38423268
DOI: 10.1016/j.mito.2024.101853 -
Nature Reviews. Molecular Cell Biology Jan 2024Mitochondria are multifaceted organelles with key roles in anabolic and catabolic metabolism, bioenergetics, cellular signalling and nutrient sensing, and programmed... (Review)
Review
Mitochondria are multifaceted organelles with key roles in anabolic and catabolic metabolism, bioenergetics, cellular signalling and nutrient sensing, and programmed cell death processes. Their diverse functions are enabled by a sophisticated set of protein components encoded by the nuclear and mitochondrial genomes. The extent and complexity of the mitochondrial proteome remained unclear for decades. This began to change 20 years ago when, driven by the emergence of mass spectrometry-based proteomics, the first draft mitochondrial proteomes were established. In the ensuing decades, further technological and computational advances helped to refine these 'maps', with current estimates of the core mammalian mitochondrial proteome ranging from 1,000 to 1,500 proteins. The creation of these compendia provided a systemic view of an organelle previously studied primarily in a reductionist fashion and has accelerated both basic scientific discovery and the diagnosis and treatment of human disease. Yet numerous challenges remain in understanding mitochondrial biology and translating this knowledge into the medical context. In this Roadmap, we propose a path forward for refining the mitochondrial protein map to enhance its discovery and therapeutic potential. We discuss how emerging technologies can assist the detection of new mitochondrial proteins, reveal their patterns of expression across diverse tissues and cell types, and provide key information on proteoforms. We highlight the power of an enhanced map for systematically defining the functions of its members. Finally, we examine the utility of an expanded, functionally annotated mitochondrial proteome in a translational setting for aiding both diagnosis of mitochondrial disease and targeting of mitochondria for treatment.
Topics: Animals; Humans; Proteome; Mitochondria; Organelles; Mitochondrial Diseases; Mass Spectrometry; Mitochondrial Proteins; Mammals
PubMed: 37773518
DOI: 10.1038/s41580-023-00650-7 -
Journal of Periodontal Research Oct 2023Periodontitis is an inflammatory and destructive disease of tooth-supporting tissue and has become the leading cause of adult tooth loss. The most central pathological... (Review)
Review
Periodontitis is an inflammatory and destructive disease of tooth-supporting tissue and has become the leading cause of adult tooth loss. The most central pathological features of periodontitis are tissue damage and inflammatory reaction. As the energy metabolism center of eukaryotic cells, mitochondrion plays a notable role in various processes, such as cell function and inflammatory response. When the intracellular homeostasis of mitochondrion is disrupted, it can lead to mitochondrial dysfunction and inability to generate adequate energy to maintain basic cellular biochemical reactions. Recent studies have revealed that mitochondrial dysfunction is closely related to the initiation and development of periodontitis. The excessive production of mitochondrial reactive oxygen species, imbalance of mitochondrial biogenesis and dynamics, mitophagy and mitochondrial DNA damage can all affect the development and progression of periodontitis. Thus, targeted mitochondrial therapy is potentially promising in periodontitis treatment. In this review, we summarize the above mitochondrial mechanism in the pathogenesis of periodontitis and discuss some potential approaches that can exert therapeutic effects on periodontitis by modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in periodontitis might provide new research directions for pathological intervention or treatment of periodontitis.
Topics: Adult; Humans; Oxidative Stress; Mitochondria; Reactive Oxygen Species; DNA, Mitochondrial; Periodontitis
PubMed: 37332252
DOI: 10.1111/jre.13152 -
Seminars in Cell & Developmental Biology 2024Mitochondria play a multitude of essential roles within mammalian cells, and understanding how they control immunity is an emerging area of study. Lymphocytes, as... (Review)
Review
Mitochondria play a multitude of essential roles within mammalian cells, and understanding how they control immunity is an emerging area of study. Lymphocytes, as integral cellular components of the adaptive immune system, rely on mitochondria for their function, and mitochondria can dynamically instruct their differentiation and activation by undergoing rapid and profound remodelling. Energy homeostasis and ATP production are often considered the primary functions of mitochondria in immune cells; however, their importance extends across a spectrum of other molecular processes, including regulation of redox balance, signalling pathways, and biosynthesis. In this review, we explore the dynamic landscape of mitochondrial homeostasis in T and B cells, and discuss how mitochondrial disorders compromise adaptive immunity.
Topics: Animals; Mitochondria; Lymphocytes; Adaptive Immunity; Signal Transduction; Homeostasis; Mammals
PubMed: 38608498
DOI: 10.1016/j.semcdb.2024.03.002 -
Signal Transduction and Targeted Therapy May 2024Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly,... (Review)
Review
Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.
Topics: Humans; Mitochondria; Mitochondrial Diseases; DNA, Mitochondrial; MicroRNAs; Neoplasms; Neurodegenerative Diseases; Cardiovascular Diseases; Animals
PubMed: 38744846
DOI: 10.1038/s41392-024-01839-8