bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒07‒17
seven papers selected by
Avinash N. Mukkala
University of Toronto

  1. Transplantation. 2022 Jul 13.
      BACKGROUND: Liver ischemia and reperfusion (IR) injury represent a major risk factor in both partial hepatectomy and liver transplantation. CCAAT/enhancer-binding protein homologous protein (CHOP) is a key regulator of cell death, its precise molecular basis in regulating hepatocyte death during liver IR has not been delineated.METHODS: Hepatocellular CHOP deficient mice were generated by bone marrow chimera models using global CHOP knockout mice. Liver partial warm ischemia model and hypoxia/reoxygenation model of primary hepatocytes were applied. Liver injury and mitophagy-related signaling pathways were investigated. IR-stressed patient liver tissues and serum samples were analyzed as well.
    RESULTS: Mice with hepatocellular CHOP deficiency exhibited alleviated cell death, decreased reactive oxygen species (ROS) expression, and enhanced mitophagy in hepatocytes after IR, confirmed by in vitro studies of hepatocytes after hypoxia/reoxygenation. Mitochondria ROS scavenge by Mito TEMPO effectively attenuated hepatocyte death and liver IR injury of wild-type mice, whereas no significant effects were observed in hepatocellular CHOP -deficient mice. CHOP depletion upregulated dynamin-related protein 1 and Beclin-1 activation in the mitochondria of hepatocytes leading to enhanced mitophagy. Following IR, increased CHOP expression and impaired mitophagy activation were observed in the livers of patients undergoing hepatectomy. N-acetyl cysteine pretreatment significantly improved the liver function of patients after surgery.
    CONCLUSIONS: IR-induced CHOP activation exacerbates ROS-mediated hepatocyte death by inhibiting dynamin-related protein 1-Beclin-1-dependent mitophagy.
  2. Int J Med Sci. 2022 ;19(6): 1036-1046
      Background: Acute lung injuries (ALI) cause disruption of the alveolar-capillary barrier and is the leading cause of death in critically ill patients. This study tested the hypothesis that the administration of freshly isolated viable allogeneic mitochondria can prevent alveolar-capillary barrier injuries at the endothelial level, as mitochondrial dysfunction of the pulmonary endothelium is a critical aspect of ALI progression. Methods: ALI was induced by intratracheal lipopolysaccharide instillation (LPS, 1mg/kg) in anesthetized rats. Mitochondria (100 µg) were isolated from the freshly harvested soleus muscles of naïve rats and stained with a green fluorescence MitoTracker™ dyne. A mitochondria or placebo solution was randomly administered into the jugular veins of the rats at 2 h and 4 h after ALI induction. An arterial blood gas analysis was done 20 h later. The animals were then sacrificed and lung tissues were harvested for analysis. Results: An IVIS Spectrum imaging system was used to obtain ex vivo heart-lung block images and track the enhancement of MitoTracker™ fluorescence in the lungs. Mitochondria transplantation significantly improved arterial oxygen contents (PaO2 and SaO2) and reduced CO2 tension in rats with ALI. Animals with mitochondrial transplants had significantly higher ATP concentrations in their lung tissues. Allogeneic mitochondria transplantation preserved alveolar-capillary barrier function, as shown by a reduction in protein levels in the bronchoalveolar lavage fluid and decreased extravasated Evans blue dyne and hemoglobin content in lung tissues. In addition, relaxation responses to acetylcholine and eNOS expression were potentiated in injured pulmonary arteries and inflammatory cells infiltration into lung tissue was reduced following mitochondrial transplantation. Conclusions: Transplantation of viable mitochondria protects the integrity of endothelial lining of the alveolar-capillary barrier, thereby improving gas exchange during the acute stages of endotoxin-induced ALI. However, the long-term effects of mitochondrial transplantation on pulmonary function recovery after ALI requires further investigation.
    Keywords:  ARDS; ATP; endothelial function; hyaline membrane; pulmonary artery
  3. Mol Neurobiol. 2022 Jul 14.
      The mitochondrial theory of aging is characterized by mitochondrial electron transport chain dysfunction. As a hallmark of aging, an increasing number of investigations have attempted to improve mitochondrial function in both aging and age-related disease. Emerging from these attempts, methods involving mitochondrial isolation, transfusion, and transplantation have taken center stage. In particular, mitochondrial transfusion refers to the administration of mitochondria from healthy tissue into the bloodstream or into tissues affected by injury, disease, or aging. In this study, methods of mitochondrial isolation and transfusion were developed and utilized. First, we found a significant decrease (p < 0.05) in the expression of mitochondrial complex proteins (I-V) in aged (12 months old) mouse brain tissue (C57BL/6 mice) in comparison to healthy young brain tissue (1 month old). To investigate whether healthy young mitochondria taken from the liver could improve mitochondrial function in older animals, we intravenously injected mitochondria isolated from young C57BL/6 mice into aged mice from the same strain. This study, for the first time, demonstrates that mitochondrial transfusion significantly (p < 0.05) improves mitochondrial function via the up-regulation of the mitochondrial complex II protein subunit SDHB in the hippocampus of aged mice. This result has identified a role for mitochondrial complex II in the aging process. Therefore, mitochondrial complex II could serve as a putative target for therapeutic interventions against aging. However, more importantly, methods of mitochondrial transfusion should be further tested to treat a variety of human diseases or disorders and to slow down or reverse processes of aging.
    Keywords:  Age-related disease; Aging; Bioenergetics; Brain; Complex II; Mitochondrial dysfunction; Mitochondrial transfusion; Neuroscience
  4. Nat Metab. 2022 Jul 11.
      Mitochondria are vital organelles with distinct morphological features and functional properties. The dynamic network of mitochondria undergoes structural and functional adaptations in response to cell-type-specific metabolic demands. Even within the same cell, mitochondria can display wide diversity and separate into functionally distinct subpopulations. Mitochondrial heterogeneity supports unique subcellular functions and is crucial to polarized cells, such as neurons. The spatiotemporal metabolic burden within the complex shape of a neuron requires precisely localized mitochondria. By travelling great lengths throughout neurons and experiencing bouts of immobility, mitochondria meet distant local fuel demands. Understanding mitochondrial heterogeneity and homeostasis mechanisms in neurons provides a framework to probe their significance to many other cell types. Here, we put forth an outline of the multifaceted role of mitochondria in regulating neuronal physiology and cellular functions more broadly.
  5. Immunity. 2022 Jul 07. pii: S1074-7613(22)00280-1. [Epub ahead of print]
      Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.
    Keywords:  FEN1; NLRP3 inflammasome; OGG1; Ox-mtDNA; VDAC; cGAS-STING; mPTP; mitochondria; mtDNA
  6. PLoS One. 2022 ;17(7): e0271606
      AIM: Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is a modification of two-stage hepatectomy profitable for patients with inoperable hepatic tumors by standard techniques. Unfortunately, initially poor postoperative outcome was associated with ALPPS, in which mitochondrial dysfunction played an essential role. Inhibition of cyclophilins has been already proposed to be efficient as a mitochondrial therapy in liver diseases. To investigate the effect of Cyclophilin D (CypD) depletion on mitochondrial function, biogenesis and liver regeneration following ALPPS a CypD knockout (KO) mice model was created.METHODS: Male wild type (WT) (n = 30) and CypD KO (n = 30) mice underwent ALPPS procedure. Animals were terminated pre-operatively and 24, 48, 72 or 168 h after the operation. Mitochondrial functional studies and proteomic analysis were performed. Regeneration rate and mitotic activity were assessed.
    RESULTS: The CypD KO group displayed improved mitochondrial function, as both ATP production (P < 0.001) and oxygen consumption (P < 0.05) were increased compared to the WT group. The level of mitochondrial biogenesis coordinator peroxisome proliferator-activated receptor γ co-activator 1-α (PGC1-α) was also elevated in the CypD KO group (P < 0.001), which resulted in the induction of the mitochondrial oxidative phosphorylation system. Liver growth increased in the CypD KO group compared to the WT group (P < 0.001).
    CONCLUSIONS: Our study demonstrates the beneficial effect of CypD depletion on the mitochondrial vulnerability following ALPPS. Based on our results we propose that CypD inhibition should be further investigated as a possible mitochondrial therapy following ALPPS.
  7. Nat Commun. 2022 Jul 15. 13(1): 4008
      The limited preservation duration of organs has contributed to the shortage of organs for transplantation. Recently, a tripling of the storage duration was achieved with supercooling, which relies on temperatures between -4 and -6 °C. However, to achieve deeper metabolic stasis, lower temperatures are required. Inspired by freeze-tolerant animals, we entered high-subzero temperatures (-10 to -15 °C) using ice nucleators to control ice and cryoprotective agents (CPAs) to maintain an unfrozen liquid fraction. We present this approach, termed partial freezing, by testing gradual (un)loading and different CPAs, holding temperatures, and storage durations. Results indicate that propylene glycol outperforms glycerol and injury is largely influenced by storage temperatures. Subsequently, we demonstrate that machine perfusion enhancements improve the recovery of livers after freezing. Ultimately, livers that were partially frozen for 5-fold longer showed favorable outcomes as compared to viable controls, although frozen livers had lower cumulative bile and higher liver enzymes.