bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒01‒30
eleven papers selected by
Avinash N. Mukkala
University of Toronto

  1. J Control Release. 2022 Jan 22. pii: S0168-3659(22)00039-6. [Epub ahead of print]
      As the major energy supplier in cells, mitochondria play a significant role in regulating cellular processes. The pathogenesis of various diseases is found to be associated with dysfunctional mitochondria, and supplement of functional mitochondria has been regarded as a potential therapeutic strategy. To achieve mitochondrial replenishment, transplantation of isolated mitochondria or utilization of cells as selective mitochondrial carrier have been developed. On the one hand, isolated mitochondria can be internalized into injured cells to restore impaired functions. On the other hand, the natural process of intercellular mitochondrial transfer can replace the dysfunctional mitochondria with functional mitochondria, providing a safe and effective way to rescue damaged tissues. Cell mediated mitochondrial transfer can serve as a promising targeted therapy with mitochondria being high-efficient biotherapeutics. In this review, we summarize the updated findings of mitochondrial delivery strategies, offering an overview of the role of mitochondria, mechanisms of intercellular mitochondrial transfer, therapeutic benefits, challenges and prospects of mitochondrial delivery. The understanding of mitochondrial delivery helps to improve the therapeutic outcomes of mitochondrial dysfunctional diseases in the future.
    Keywords:  Delivery; Mitochondria; Regenerative potential; Stem cells; Transplantation
  2. J Biochem. 2022 Jan 26. pii: mvac005. [Epub ahead of print]
      In addition to the cytoplasmic translation system, eukaryotic cells house additional protein synthesis machinery in mitochondria. The importance of this in organello translation is exemplified by clinical pathologies associated with mutations in mitochondrial translation factors. Although a detailed understanding of mitochondrial translation has long been awaited, quantitative, comprehensive, and spatiotemporal measurements have posed analytic challenges. The recent development of novel approaches for studying mitochondrial protein synthesis has overcome these issues and expands our understanding of the unique translation system. Here, we review the current technologies for the investigation of mitochondrial translation and the insights provided by their application.
    Keywords:  FUNCAT; Mitochondria; Mitoribosome; Ribosome profiling; Translation
  3. Life Sci. 2022 Jan 19. pii: S0024-3205(22)00038-8. [Epub ahead of print] 120338
      BACKGROUND AND PURPOSE: Ischemic reperfusion (I/R) injury causes a wide array of functional and structure alternations of mitochondria, associated with oxidative stress and increased the severity of injury. Despite the previous evidence for N-acetyl L-cysteine (NAC) provide neuroprotection after I/R injury, it is unknown to evaluate the effect of NAC on altered mitochondrial autophagy forms an essential axis to impaired mitochondrial quality control in cerebral I/R injury.METHODS: Male wistar rats subjected to I/R injury were used as transient Middle Cerebral Artery Occlusion (tMCAO) model. After I/R injury, the degree of cerebral tissue injury was detected by infarct volume, H&E staining and behavioral assessment. We also performed mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometry and mitochondrial respiratory complexes to evaluate the mitochondrial dysfunction. Finally, we performed the western blotting analysis to measure the apoptotic and autophagic marker.
    RESULTS: We found that NAC administration significantly ameliorates brain injury, improves neurobehavioral outcome, decreases neuroinflammation and mitochondrial mediated oxidative stress. We evaluated the neuroprotective effect of NAC against neuronal apoptosis by assessing its ability to sustained mitochondrial integrity and function. Further studies revealed that beneficial effects of NAC is through targeting the mitochondrial autophagy via regulating the GSK-3β/Drp1mediated mitochondrial fission and inhibiting the expression of beclin-1 and conversion of LC3, as well as activating the p-Akt pro-survival pathway.
    CONCLUSION: Our results suggest that NAC exerts neuroprotective effects to inhibit the altered mitochondrial changes and cell death in I/R injury via regulation of p-GSK-3β mediated Drp-1 translocation to the mitochondria.
    Keywords:  Apoptosis; Autophagy; Drp-1; Ischemic-stroke; Mitochondria
  4. FEBS Lett. 2022 Jan 28.
      Mitochondria are associated with various cellular activities critical to homeostasis, particularly in the nervous system. The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles in ensuring that varying energetic demands are rapidly met to maintain neuronal and axonal energy homeostasis. Recent evidence associates ageing and neurodegeneration with anomalous neuronal metabolism, as age-dependent alterations of neuronal metabolism are now believed to occur prior to neurodegeneration. The brain has a high energy demand, which makes it particularly sensitive to mitochondrial dysfunction. Distinct cellular events causing oxidative stress or disruption of metabolism and mitochondrial homeostasis can trigger a neuropathology. This review explores the bioenergetic hypothesis for the neurodegenerative pathomechanisms, discussing factors leading to age-related brain hypometabolism and its contribution to cognitive decline. Recent research on the mitochondrial network in healthy nervous system cells, its response to stress and how it is affected by pathology, as well as current contributions to novel therapeutic approaches will be highlighted.
    Keywords:  Alzheimer; Huntington; Parkinson; ROS; ageing; axon; mitochondria; mitophagy; neurodegeneration; neuron
  5. Mitochondrion. 2022 Jan 22. pii: S1567-7249(22)00006-X. [Epub ahead of print]
      Several drug targets have been amenable to drug discovery pursuit not until the characterization of the mitochondrial permeability transition pore (MPTP), a pore with an undefined molecular identity that forms on the inner mitochondrial membrane upon mitochondrial permeability transition (MPT) under the influence of calcium overload and oxidative stress. The opening of the pore which is presumed to cause cell death in certain human diseases also has implications under physiological parlance. The mitochondrial community has witnessed many protein candidates such as; voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), Mitochondrial phosphate carrier (PiC), Spastic Paralegin (SPG7), disordered proteins, and F1Fo ATPase. Also, different models for this pore have been postulated in the last six decades since it was characterized but genetic studies have cast out most of these candidates with only F1Fo ATPase currently under intense argument. Cyclophilin D (CyPD) remains the widely accepted positive regulator of the MPTP known to date, but no drug candidate has emerged as its inhibitor, raising concern issues for therapeutics. Thus, in this review, we discuss various models of MPTP reported with the hope of stimulating further research in this field. We went beyond the classical description of the MPTP to ascribe a 'two-edged sword property' to the pore for therapeutic function in human disease because its inhibition and activation have pharmacological relevance. We identified putative proteins upstream to CyPD that can regulate its activity and prevent cell deaths in neurodegenerative disease and ischemia-reperfusion injury.
    Keywords:  Cyclophilin D; Ischemia Reperfusion Injury; Mitochondrial permeability transition pore (MPTP); Neurodegenerative disease; drug discovery; mitochondrial permeability transition (MPT)
  6. Crit Care Med. 2022 Jan 24.
      OBJECTIVES: Recent publications have shown that mitochondrial dynamics can govern the quality and quantity of extracellular mitochondria subsequently impacting immune phenotypes. This study aims to determine if pathologic mitochondrial fission mediated by Drp1/Fis1 interaction impacts extracellular mitochondrial content and macrophage function in sepsis-induced immunoparalysis.DESIGN: Laboratory investigation.
    SETTING: University laboratory.
    SUBJECTS: C57BL/6 and BALB/C mice.
    INTERVENTIONS: Using in vitro and murine models of endotoxin tolerance (ET), we evaluated changes in Drp1/Fis1-dependent pathologic fission and simultaneously measured the quantity and quality of extracellular mitochondria. Next, by priming mouse macrophages with isolated healthy mitochondria (MC) and damaged mitochondria, we determined if damaged extracellular mitochondria are capable of inducing tolerance to subsequent endotoxin challenge. Finally, we determined if inhibition of Drp1/Fis1-mediated pathologic fission abrogates release of damaged extracellular mitochondria and improves macrophage response to subsequent endotoxin challenge.
    MEASUREMENTS AND MAIN RESULTS: When compared with naïve macrophages (NMs), endotoxin-tolerant macrophages (ETM) demonstrated Drp1/Fis1-dependent mitochondrial dysfunction and higher levels of damaged extracellular mitochondria (Mitotracker-Green + events/50 μL: ETM = 2.42 × 106 ± 4,391 vs NM = 5.69 × 105 ± 2,478; p < 0.001). Exposure of NMs to damaged extracellular mitochondria (MH) induced cross-tolerance to subsequent endotoxin challenge, whereas MC had minimal effect (tumor necrosis factor [TNF]-α [pg/mL]: NM = 668 ± 3, NM + MH = 221 ± 15, and NM + Mc = 881 ± 15; p < 0.0001). Inhibiting Drp1/Fis1-dependent mitochondrial fission using heptapeptide (P110), a selective inhibitor of Drp1/Fis1 interaction, improved extracellular mitochondrial function (extracellular mitochondrial membrane potential, JC-1 [R/G] ETM = 7 ± 0.5 vs ETM + P110 = 19 ± 2.0; p < 0.001) and subsequently improved immune response in ETMs (TNF-α [pg/mL]; ETM = 149 ± 1 vs ETM + P110 = 1,150 ± 4; p < 0.0001). Similarly, P110-treated endotoxin tolerant mice had lower amounts of damaged extracellular mitochondria in plasma (represented by higher extracellular mitochondrial membrane potential, TMRM/MT-G: endotoxin tolerant [ET] = 0.04 ± 0.02 vs ET + P110 = 0.21 ± 0.02; p = 0.03) and improved immune response to subsequent endotoxin treatment as well as cecal ligation and puncture.
    CONCLUSIONS: Inhibition of Drp1/Fis1-dependent mitochondrial fragmentation improved macrophage function and immune response in both in vitro and in vivo models of ET. This benefit is mediated, at least in part, by decreasing the release of damaged extracellular mitochondria, which contributes to endotoxin cross-tolerance. Altogether, these data suggest that alterations in mitochondrial dynamics may play an important role in sepsis-induced immunoparalysis.
  7. J Physiol. 2022 Jan 24.
      KEY POINTS: Denervation is an experimental model of peripheral neuropathies as well as muscle disuse, and it helps us understand some aspects of the sarcopenia of aging. Muscle disuse is associated with reduced mitochondrial content and function, leading to metabolic impairments within the tissue. Although the processes that regulate mitochondrial biogenesis are understood, those that govern mitochondrial breakdown (i.e., mitophagy) are not well characterized in this context. Autophagy and mitophagy flux, measured up to the point of the lysosome (pre-lysosomal flux rates), were increased in the early stages of denervation, along with mitochondrial dysfunction, but were reduced at later time points when the degree of muscle atrophy was highest. Denervation led to progressive increases in lysosomal proteins to accommodate mitophagy flux, yet evidence for lysosomal impairment at later stages may limit the removal of dysfunctional mitochondria, stimulate reactive oxygen species signaling, and reduce muscle health as denervation time progresses.ABSTRACT: Deficits in skeletal muscle mitochondrial content and quality are observed following denervation-atrophy. This is due to alterations in the biogenesis of new mitochondria as well as their degradation via mitophagy. The regulation of autophagy and mitophagy over the course of denervation (Den) remains unknown. Further, the time-dependent changes in lysosome content, the end-stage organelle for mitophagy, remains unexplored. Here, we studied autophagic as well as mitophagic pre-lysosomal flux in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria from rat muscle subjected to Den for 1, 3, or 7 days. We also assessed flux at 1-day post-denervation in transgenic mt-keima mice. Markers of mitochondrial content were reduced at 7 days following Den, and Den further resulted in rapid decrements in mitochondrial respiration, along with increased ROS emission. Pre-lysosomal autophagy flux was upregulated at 1- and 3-days post-Den but was reduced compared to time-matched sham-operated controls at 7-days post-Den. Similarly, pre-lysosomal mitophagy flux was enhanced in SS mitochondria as early as 1- and 3-days of Den but decreased in both SS and IMF subfractions following 7 days of Den. Lysosome protein content and transcriptional regulators TFEB and TFE3 were progressively enhanced with Den, an adaptation designed to enhance autophagic capacity. However, evidence for lysosome dysfunction was apparent by 7 days, which may limit degradation capacity. This may contribute to an inability to clear dysfunctional mitochondria and increased ROS signaling, thereby accelerating muscle atrophy. Thus, therapeutic targeting of lysosome function may help to maintain autophagy and muscle health during conditions of muscle disuse or denervation. Abstract figure legend This study investigates the temporal regulation of the autophagy-lysosome system in rat skeletal muscle following neuromuscular denervation (Den) with a focus on mitochondrial decay through mitophagy. We show that mitochondrial dysfunction is time-dependant, with elevations at 3-days post-Den and further at 7 days, preceding decrements in mitochondrial protein content. Deficits in mitochondrial content may be explained by prior elevations in mitophagy as early as 1- and 3-days post-Den, but these elevations were bi-phasic, returning to lower values by 7-days post-Den. To meet the demands of increased autophagy, lysosome protein content was progressively upregulated with 3- and 7-day of Den, but evidence of lysosome dysfunction was evident, and this could impede the removal of poor-quality mitochondria. Overall, these changes in the autophagy-lysosome system following neuromuscular denervation and provide insight into the processes that contribute to Den-induced muscle atrophy. Representative graphs are Den/Sham, with the dotted line representing sham-operated control values. This article is protected by copyright. All rights reserved.
    Keywords:  TFEB; atrophy; lysosome dysfunction; mitochondrial dysfunction; reactive oxygen species
  8. Redox Biol. 2022 Jan 18. pii: S2213-2317(22)00015-5. [Epub ahead of print]50 102243
      Metabolic adaptation and signal integration in response to hypoxic conditions is mainly regulated by hypoxia-inducible factors (HIFs). At the same time, hypoxia induces ROS formation and activates the unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress. However, whether ER stress would affect the hypoxia response remains ill-defined. Here we report that feeding mice a high fat diet causes ER stress and attenuates the response to hypoxia. Mechanistically, ER stress promotes HIF-1α and HIF-2α degradation independent of ROS, Ca2+, and the von Hippel-Lindau (VHL) pathway, involving GSK3β and the ubiquitin ligase FBXW1A/βTrCP. Thereby, we reveal a previously unknown function of the GSK3β/HIFα/βTrCP1 axis in ER homeostasis and demonstrate that inhibition of the HIF-1 and HIF-2 response and genetic deficiency of GSK3β affects proliferation, migration, and sensitizes cells for ER stress promoted apoptosis. Vice versa, we show that hypoxia affects the ER stress response mainly through the PERK-arm of the UPR. Overall, we discovered previously unrecognized links between the HIF pathway and the ER stress response and uncovered an essential survival pathway for cells under ER stress.
    Keywords:  ER stress; HIF-1α; HIF-2α; Mild hypoxia; UPR
  9. Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01805-2. [Epub ahead of print]38(4): 110290
      Invaginations of the mitochondrial inner membrane, termed cristae, are hubs for oxidative phosphorylation. The mitochondrial contact site and cristae organizing system (MICOS) and the dimeric F1Fo-ATP synthase play important roles in controlling cristae architecture. A fraction of the MICOS core subunit Mic10 is found in association with the ATP synthase, yet it is unknown whether this interaction is of relevance for mitochondrial or cellular functions. Here, we established conditions to selectively study the role of Mic10 at the ATP synthase. Mic10 variants impaired in MICOS functions stimulate ATP synthase oligomerization like wild-type Mic10 and promote efficient inner membrane energization, adaptation to non-fermentable carbon sources, and respiratory growth. Mic10's functions in respiratory growth largely depend on Mic10ATPsynthase, not on Mic10MICOS. We conclude that Mic10 plays a dual role as core subunit of MICOS and as partner of the F1Fo-ATP synthase, serving distinct functions in cristae shaping and respiratory adaptation and growth.
    Keywords:  ATP synthase; MICOS; Mic10; cristae organization; inner membrane; membrane architecture; membrane potential; metabolic adaptation; mitochondria; respiration
  10. FASEB J. 2022 Feb;36(2): e22146
      Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence human development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in knowledge. This meta-analysis systematically examined four domains and six subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedge's g) of sex differences were computed for each measure using data in 2258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women's WAT and isolated leukocyte subpopulations (g = 0.20, χ2 p = .01), and higher ROS production in men's skeletal muscle (g = 0.49, χ2 p < .0001). Sex differences showed weak to no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -.17, p < .001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.
    Keywords:  mitochondrion; mtDNAcn; respirometry; sex differences; sexual dimorphism
  11. Nanotoxicology. 2022 Jan 25. 1-22
      Broad applications of cobalt nanoparticles (CoNPs) have raised increased concerns regarding their potential toxicity. However, the underlining mechanisms of their toxicity have yet to be characterized. Here, we demonstrated that CoNPs reduced cell viability and induced membrane leakage. CoNPs induced oxidative stress, as indicated by the generation of reactive oxygen species (ROS) secondary to the increased expression of hypoxia-induced factor 1 alpha. Moreover, CoNPs led to mitochondrial damage, including generation of mitochondrial ROS, reduction in ATP content, morphological damage and autophagy. Interestingly, exogenous mitochondria were observed between neurons and astrocytes upon CoNPs exposure. Concomitantly, tunneling nanotubes (TNTs)-like structures were observed between neurons and astrocytes upon CoNPs exposure. These structures were further verified to be TNTs as they were found to be F-actin rich and lacking tubulin. We then demonstrated that TNTs were utilized for mitochondrial transfer between neurons and astrocytes, suggesting a novel crosstalk phenomenon between these cells. Moreover, we found that the inhibition of TNTs (using actin-depolymerizing drug latrunculin B) intensified apoptosis triggered by CoNPs. Therefore, we demonstrate, for the first time, that the inhibition of intercellular mitochondrial transfer via TNTs aggravates CoNPs-induced cellular and mitochondrial toxicity in neuronal cells, implying a novel intercellular protection mechanism in response to nanoparticle exposure.
    Keywords:  Cobalt nanoparticles (CoNPs); astrocytes; mitochondrial transfer; neurotoxicity; tunneling nanotubes (TNTs)