bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2020‒08‒16
ten papers selected by
Avinash N. Mukkala
University of Toronto


  1. Clin Sci (Lond). 2020 Aug 14. pii: CS20200530. [Epub ahead of print]
    Ma H, Jiang T, Tang W, Ma Z, Pu K, Xu F, Chang H, Zhao G, Gao W, Li Y, Wang Q.
      Diabetes-associated cognitive impairment (DACI) can increase the risk of major cardiovascular events and death. Neuronal functionality is highly dependent on mitochondria and emerging evidence has shown that mitochondrial transplantation is a potential and effective strategy that can reduce brain injury and associated disorders. Platelets are abundant in blood and can be considered a readily available source of small-size mitochondria. These cells can be easily acquired from the peripheral blood with minimal invasion via simple venipuncture. The present study aimed to investigate whether transplantation of platelet-derived mitochondria (Mito-Plt) could improve DACI. Cognitive behaviors were assessed using the Morris water maze test in db/db mice. The results demonstrated that Mito-Plt was internalized into hippocampal neurons 24 h following intracerebroventricular injection. Importantly, one month following Mito-Plt transplantation, DACI was alleviated in db/db mice and the effect was accompanied with increased mitochondrial number, restored mitochondrial function, attenuated oxidative stress and neuronal apoptosis, as well as decreased accumulation of Aβ and Tau in the hippocampus. Taken together, the data demonstrated that transplantation of Mito-Plt attenuated cognitive impairment and mitochondrial dysfunction in db/db mice. This method may be a potential therapeutic application for the treatment of DACI.
    Keywords:  cognitive impairment; hippocampus; mitochondrial transplantation; oxidative stress; platelet; type 2 diabetes
    DOI:  https://doi.org/10.1042/CS20200530
  2. Mol Cell Biochem. 2020 Aug 14.
    Visavadiya NP, Pena GS, Khamoui AV.
      Hepatic mitochondrial function loss is associated with cancer cachexia pathology in vivo. Here, we examined if hepatic mitochondrial defects observed in vivo in the cachexic liver also recapitulate during the in vitro treatment of mouse hepatocytes with tumor conditioned media. In vitro experiments were combined with proteome-wide expression analysis of cachexic liver tissue curated for mitochondrial dynamics and quality control proteins, to determine the fidelity of hepatic mitochondrial maladaptation in cancer cachexia pathology. AML12 hepatocytes were exposed to colon-26 (C26) and Lewis lung carcinoma (LLC) conditioned media for 6-72 h and assayed for cell viability, membrane potential, respiratory function, H2O2 production, total ROS/RNS, and mitochondrial dynamics and quality control proteins by immunoblotting. Liver tissue from cachexic C26 mice was analyzed by TMT-based quantitative proteomics for in vivo comparison. Cell viability, membrane potential, H2O2 production, total ROS/RNS, and respiration were decreased 48-72 h after exposure to C26 and/or LLC. Protein expression of treated hepatocytes and cachexic liver tissue showed altered mitochondrial dynamics and quality control, in a manner that suggests limited fusion and content mixing, but also impaired ability to fragment and clear damaged mitochondria. Two strategies to maintain mitochondrial health, therefore, may not be functioning sufficiently in the cachexic liver. Together these findings imply adverse effects of C26 and LLC exposure on hepatocyte health, due to impaired mitochondrial function and remodeling. Exposure of mouse hepatocytes to tumor conditioned media models aspects of cachexic liver mitochondria dysfunction in vivo and validates the importance of hepatic mitochondrial maladaptation in cancer cachexia pathology.
    Keywords:  Cancer cachexia; Hepatocyte; High-resolution respirometry; Liver cell culture; Mitochondria
    DOI:  https://doi.org/10.1007/s11010-020-03882-9
  3. Science. 2020 Aug 14. 369(6505): 858-862
    Iwata R, Casimir P, Vanderhaeghen P.
      The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.
    DOI:  https://doi.org/10.1126/science.aba9760
  4. Oxid Med Cell Longev. 2020 ;2020 3549704
    Gu C, Li L, Huang Y, Qian D, Liu W, Zhang C, Luo Y, Zhou Z, Kong F, Zhao X, Liu H, Gao P, Chen J, Yin G.
      Ischemia-reperfusion injury is the second most common injury of the spinal cord and has the risk of neurological dysfunction and paralysis, which can seriously affect patient quality of life. Salidroside (Sal) is an active ingredient extracted from Herba Cistanche with a variety of biological attributes such as antioxidant, antiapoptotic, and neuroprotective activities. Moreover, Sal has shown a protective effect in ischemia-reperfusion injury of the liver, heart, and brain, but its effect in ischemia-reperfusion injury of the spinal cord has not been elucidated. Here, we demonstrated for the first time that Sal pretreatment can significantly improve functional recovery in mice after spinal cord ischemia-reperfusion injury and significantly inhibit the apoptosis of neurons both in vivo and in vitro. Neurons have a high metabolic rate, and consequently, mitochondria, as the main energy-supplying suborganelles, become the main injury site of spinal cord ischemia-reperfusion injury. Mitochondrial pathway-dependent neuronal apoptosis is increasingly confirmed by researchers; therefore, Sal's effect on mitochondria naturally attracted our attention. By means of a range of experiments both in vivo and in vitro, we found that Sal can reduce reactive oxygen species production through antioxidant stress to reduce mitochondrial permeability and mitochondrial damage, and it can also enhance the PINK1-Parkin signaling pathway and promote mitophagy to eliminate damaged mitochondria. In conclusion, our results show that Sal is beneficial to the protection of spinal cord neurons after ischemia-reperfusion injury, mainly by reducing apoptosis associated with the mitochondrial-dependent pathway, among which Sal's antioxidant and autophagy-promoting properties play an important role.
    DOI:  https://doi.org/10.1155/2020/3549704
  5. Mitochondrion. 2020 Aug 09. pii: S1567-7249(20)30170-7. [Epub ahead of print]
    Purushottam Dharaskar S, Paithankar K, Kanugovi Vijayavittal A, Shabbir Kara H, Amere Subbarao S.
      Mitochondria play a central role in regulating cellular energy metabolism. However, the present understanding of mitochondria has changed from its unipotent functions to pluripotent and insists on understanding the role of mitochondria not only in regulating the life and death of cells, but in pathological conditions such as cancer. Unlike other cellular organelles, subtle alterations in mitochondrial organization may significantly influence the balance between metabolic networks and cellular behavior. Therefore, the delicate balance between the fusion and fission dynamics of mitochondrion can indicate cell fate. Here, we present mitochondrial chaperone TRAP1 influence on mitochondrial architecture and its correlation with tumor growth and metastasis. We show that TRAP1 overexpression (TRAP1 OE) promotes mitochondrial fission, whereas, TRAP1 knockdown (TRAP1 KD) promotes mitochondrial fusion. Interestingly, TRAP1 OE or KD had a negligible effect on mitochondrial integrity. However, TRAP1 OE cells exhibited enhanced proliferative potential, while TRAP1 KD cells showing increased doubling time. Further, TRAP1 dependent mitochondrial dynamic alterations appeared to be unique since mitochondrial localization of TRAP1 is a mandate for dynamic changes. The expression patterns of fusion and fission genes have failed to correlate with TRAP1 expression, indicating a possibility that the dynamic changes can be independent of these genes. In agreement with enhanced proliferative potential, TRAP1 OE cells also exhibited enhanced migration in vitro and tumor metastasis in vivo. Further, TRAP1 OE cells showed altered homing properties, which may challenge site-specific anticancer treatments. Our findings unravel the TRAP1 role in tumor metastasis, which is in addition to altered energy metabolism.
    DOI:  https://doi.org/10.1016/j.mito.2020.08.001
  6. Redox Biol. 2020 Jul 27. pii: S2213-2317(20)30866-1. [Epub ahead of print]36 101661
    Wu H, Wei H, Zhang D, Sehgal SA, Zhang D, Wang X, Qin Y, Liu L, Chen Q.
      Both iron metabolism and mitophagy, a selective mitochondrial degradation process via autolysosomal pathway, are fundamental for the cellular well-being. Mitochondria are the major site for iron metabolism, especially the biogenesis of iron-sulfur clusters (ISCs) via the mitochondria-localized ISCs assembly machinery. Here we report that mitochondrial ISCs biogenesis is coupled with receptor-mediated mitophagy in mammalian cells. Perturbation of mitochondrial ISCs biogenesis, either by depleting iron with the iron chelator or by knocking down the core components of the mitochondrial ISCs assembly machinery, triggers FUNDC1-dependent mitophagy. IRP1, one of the cellular iron sensors to maintain iron homeostasis, is crucial for iron stresses induced mitophagy. Knockdown of IRP1 disturbed iron stresses induced mitophagy. Furthermore, IRP1 could bind to a newly characterized IRE in the 5' untranslated region of the Bcl-xL mRNA and suppress its translation. Bcl-xL is an intrinsic inhibitory protein of the mitochondrial phosphatase PGAM5, which catalyzes the dephosphorylation of FUNDC1 for mitophagy activation. Alterations of the IRP1/Bcl-xL axis navigate iron stresses induced mitophagy. We conclude that ISCs serve as physiological signals for mitophagy activation, thus coupling mitophagy with iron metabolism.
    Keywords:  Bcl-xL; FUNDC1; ISCs; Mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2020.101661
  7. Stem Cell Reports. 2020 Jul 30. pii: S2213-6711(20)30290-3. [Epub ahead of print]
    Kumar M, Acevedo-Cintrón J, Jhaldiyal A, Wang H, Andrabi SA, Eacker S, Karuppagounder SS, Brahmachari S, Chen R, Kim H, Ko HS, Dawson VL, Dawson TM.
      Mutations and loss of activity in PARKIN, an E3 ubiquitin ligase, play a role in the pathogenesis of Parkinson's disease (PD). PARKIN regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. Defects in mitophagy have been hypothesized to play a predominant role in the loss of dopamine (DA) neurons in PD. Here, we show that although there are defects in mitophagy in human DA neurons lacking PARKIN, the mitochondrial deficits are primarily due to defects in mitochondrial biogenesis that are driven by the upregulation of PARIS and the subsequent downregulation of PGC-1α. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without affecting the deficits in mitophagy. These results highlight the importance mitochondrial biogenesis versus mitophagy in the pathogenesis of PD due to inactivation or loss of PARKIN in human DA neurons.
    Keywords:  PARIS; PARKIN; PGC-1α; Parkinson’s disease; ZNF746; dopamine; human IPSC; isogenic; mitochondrial biogenesis; mitophagy
    DOI:  https://doi.org/10.1016/j.stemcr.2020.07.013
  8. Sci Rep. 2020 Aug 11. 10(1): 13523
    Kim HS, Ren G, Kim T, Bhatnagar S, Yang Q, Bahk YY, Kim JA.
      Autophagy, an integral part of the waste recycling process, plays an important role in cellular physiology and pathophysiology. Impaired autophagic flux causes ectopic lipid deposition, which is defined as the accumulation of lipids in non-adipose tissue. Ectopic lipid accumulation is observed in patients with cardiometabolic syndrome, including obesity, diabetes, insulin resistance, and cardiovascular complications. Metformin is the first line of treatment for type 2 diabetes, and one of the underlying mechanisms for the anti-diabetic effect of metformin is mediated by the stimulation of AMP-activated protein kinase (AMPK). Because the activation of AMPK is crucial for the initiation of autophagy, we hypothesize that metformin reduces the accumulation of lipid droplets by increasing autophagic flux in vascular endothelial cells. Incubation of vascular endothelial cells with saturated fatty acid (SFA) increased the accumulation of lipid droplets and impaired autophagic flux. We observed that the accumulation of lipid droplets was reduced, and the autophagic flux was enhanced by treatment with metformin. The knock-down of AMPKα by using siRNA blunted the effect of metformin. Furthermore, treatment with SFA or inhibition of autophagy increased leukocyte adhesion, whereas treatment with metformin decreased the SFA-induced leukocyte adhesion. The results suggest a novel mechanism by which metformin protects vascular endothelium from SFA-induced ectopic lipid accumulation and pro-inflammatory responses. In conclusion, improving autophagic flux may be a therapeutic strategy to protect endothelial function from dyslipidemia and diabetic complications.
    DOI:  https://doi.org/10.1038/s41598-020-70347-w
  9. Am J Physiol Endocrinol Metab. 2020 Aug 10.
    Merry TL, Chan A, Woodhead JST, Reynolds JC, Kumaga H, Kim SJ, Lee C.
      Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metabolo-protective properties. The 12S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, while the other seven MDPs, [humanin and small humanin-like peptides (SHLP) 1-6] are encoded by the 16S ribosomal RNA gene. Here we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes and aging are associated with lower circulating MDPs. Whereas, in humans, muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Further, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell, and to distal tissues, to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metabolo-protective properties of MDPs can be harnessed into therapies for metabolic disease.
    Keywords:  MOTS-c; Mitokine; ageing; mitochondria; mitochondrial derived peptides
    DOI:  https://doi.org/10.1152/ajpendo.00249.2020
  10. Redox Biol. 2020 Jul 03. pii: S2213-2317(20)30827-2. [Epub ahead of print]36 101622
    Maity J, Deb M, Greene C, Das H.
      To define the regulatory role of Kruppel-like factor 2 (KLF2) during osteoblast (OB) differentiation of dental pulp-derived stem cell (DPSC)s, herein, we show that the levels of KLF2 and autophagy-related molecules were significantly increased in differentiated cells. Gain-of-function and loss-of-function approaches of KLF2 confirmed that KLF2 modulated autophagic and OB differentiation-related molecules. In addition, knockdown of the autophagic molecule (ATG7 or BECN1) in DPSCs resulted in reduced levels of KLF2 and OB differentiation-related molecules. Conversely, the induction of autophagy increased levels of KLF2 and OB differentiation-related molecules. Moreover, OB differentiation induced mitophagy and mitochondrial membrane potential-related molecules. In addition, OB differentiation reduced the generation of total and mitochondrial ROS productions and induced intracellular Ca2+ production. Measurements of glycolysis and oxidative phosphorylation simultaneously in live cells revealed that OB differentiation decreased the oxygen consumption rate, which is an indicator of mitochondrial respiration and reduced the level of ATP production. Furthermore, flux analysis also revealed that OB differentiation increased the extracellular acidification rate (ECAR) in the non-glycolytic acidification, and the glycolytic capacity conditions, increasing the lactate production and reducing the metabolic activity of the cells. Thus, a metabolic shift from mitochondrial respiration to the glycolytic pathway was observed during OB differentiation. Finally, chromatin immunoprecipitation (ChIP) analysis confirmed that the KLF2 and active epigenetic marks (H3K27Ac and H3K4me3) were upregulated in the promoter region of ATG7 during OB differentiation. These results provide evidence that the mitophagy process is important during OB differentiation, and KLF2 critically regulates it.
    Keywords:  Autophagy; DPSC; Histone acetylation; Histone methylation; KLF2; Mitophagy; OB differentiation
    DOI:  https://doi.org/10.1016/j.redox.2020.101622