bims-tofagi Biomed News
on Mitophagy
Issue of 2023–11–19
eight papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea
  1. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.
  2. Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation.
  3. FOXO1 reduces STAT3 activation and causes impaired mitochondrial quality control in diabetic cardiomyopathy.
  4. Role of mitophagy in ocular neurodegeneration.
  5. PHB2 Alleviates Neurotoxicity of Prion Peptide PrP106-126 via PINK1/Parkin-Dependent Mitophagy.
  6. FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment.
  7. A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan.
  8. Mitochondrial dysfunction in Parkinson's disease - a key disease hallmark with therapeutic potential.
  1. Nat Commun. 2023 Nov 13. 14(1): 7295
    Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.
    Tracy-Shi Zhang Fang, Yu Sun, Andrew C Pearce, Simona Eleuteri, Mark Kemp, Christopher A Luckhurst, Rachel Williams, Ross Mills, Sarah Almond, Laura Burzynski, Nóra M Márkus, Christopher J Lelliott, Natasha A Karp, David J Adams, Stephen P Jackson, Jin-Feng Zhao, Ian G Ganley, Paul W Thompson, Gabriel Balmus, David K Simon.
      Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria ("mitophagy") by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.
    DOI:  https://doi.org/10.1038/s41467-023-42876-1
  2. Cell Death Dis. 2023 11 11. 14(11): 735
    Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation.
    Jinfa Ma, Lei Liu, Lu Song, Jianghong Liu, Lingyao Yang, Quan Chen, Jane Y Wu, Li Zhu.
      Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into mitochondria. In addition, whether mitochondrial damage is caused by mitochondrial mislocalization of TDP-43 or a side effect of mitochondria-mediated TDP-43 degradation remains to be investigated. Here, our bioinformatical analyses reveal that mitophagy receptor gene FUNDC1 is co-expressed with TDP-43, and both TDP-43 and FUNDC1 expression is correlated with genes associated with mitochondrial protein import pathway in brain samples of patients diagnosed with TDP-43 proteinopathy. FUNDC1 promotes mitochondrial translocation of TDP-43 possibly by promoting TDP-43-TOM70 and DNAJA2-TOM70 interactions, which is independent of the LC3 interacting region of FUNDC1 in cellular experiments. In the transgenic fly model of TDP-43 proteinopathy, overexpressing FUNDC1 enhances TDP-43 induced mitochondrial damage, whereas down-regulating FUNDC1 reverses TDP-43 induced mitochondrial damage. FUNDC1 regulates mitochondria-mediated TDP-43 degradation not only by regulating mitochondrial TDP-43 import, but also by increasing LONP1 level and by activating mitophagy, which plays important roles in cytosolic TDP-43 clearance. Together, this study not only uncovers the mechanism of mitochondrial TDP-43 import, but also unravels the active role played by mitochondria in regulating TDP-43 homeostasis.
    DOI:  https://doi.org/10.1038/s41419-023-06261-6
  3. Diabetes Obes Metab. 2023 Nov 14.
    FOXO1 reduces STAT3 activation and causes impaired mitochondrial quality control in diabetic cardiomyopathy.
    Lu Zhou, Wating Su, Yafeng Wang, Yuefu Zhang, Zhongyuan Xia, Shaoqing Lei.
       AIMS: To investigate the role of FOXO1 in STAT3 activation and mitochondrial quality control in the diabetic heart.
    METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats by a single intraperitoneal injection of 60 mg · kg-1 streptozotocin (STZ), while type 2 diabetes mellitus (T2DM) was induced in rats with a high-fat diet through intraperitoneal injection of 35 mg · kg-1 STZ. Primary neonatal mouse cardiomyocytes and H9c2 cells were exposed to low glucose (5.5 mM) or high glucose (HG; 30 mM) with or without treatment with the FOXO1 inhibitor AS1842856 (1 μM) for 24 hours. In addition, the diabetic db/db mice (aged 8 weeks) and sex- and age-matched non-diabetic db/+ mice were treated with vehicle or AS1842856 by oral gavage for 15 days at a dose of 5 mg · kg-1  · d-1 .
    RESULTS: Rats with T1DM or T2DM had excessive cardiac FOXO1 activation, accompanied by decreased STAT3 activation. Immunofluorescence and immunoprecipitation analysis showed colocalization and association of FOXO1 and STAT3 under basal conditions in isolated cardiomyocytes. Selective inhibition of FOXO1 activation by AS1842856 or FOXO1 siRNA transfection improved STAT3 activation, mitophagy and mitochondrial fusion, and decreased mitochondrial fission in isolated cardiomyocytes exposed to HG. Transfection with STAT3 siRNA further reduced mitophagy, mitochondrial fusion and increased mitochondrial fission in HG-treated cardiomyocytes. AS1842856 alleviated cardiac dysfunction, pathological damage and improved STAT3 activation, mitophagy and mitochondrial dynamics in diabetic db/db mice. Additionally, AS1842856 improved mitochondrial function indicated by increased mitochondrial membrane potential and adenosine triphosphate production and decreased mitochondrial reactive oxygen species production in isolated cardiomyocytes exposed to HG.
    CONCLUSIONS: Excessive FOXO1 activation during diabetes reduces STAT3 activation, with subsequent impairment of mitochondrial quality, ultimately promoting the development of diabetic cardiomyopathy.
    Keywords:  FOXO1; STAT3; diabetic cardiomyopathy; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.1111/dom.15369
  4. Front Neurosci. 2023 ;17 1299552
    Role of mitophagy in ocular neurodegeneration.
    Calvin D Brooks, Bindu Kodati, Dorota L Stankowska, Raghu R Krishnamoorthy.
      Neurons in the central nervous system are among the most metabolically active cells in the body, characterized by high oxygen consumption utilizing glucose both aerobically and anaerobically. Neurons have an abundance of mitochondria which generate adequate ATP to keep up with the high metabolic demand. One consequence of the oxidative phosphorylation mechanism of ATP synthesis, is the generation of reactive oxygen species which produces cellular injury as well as damage to mitochondria. Mitochondria respond to injury by fusion which serves to ameliorate the damage through genetic complementation. Mitochondria also undergo fission to meet an increased energy demand. Loss of mitochondria is also compensated by increased biogenesis to generate new mitochondria. Damaged mitochondria are removed by mitophagy, an autophagic process, in which damaged mitochondria are surrounded by a membrane to form an autophagosome which ultimately fuses with the lysosome resulting in degradation of faulty mitochondria. Dysregulation of mitophagy has been reported in several central nervous system disorders, including, Alzheimer's disease and Parkinson's disease. Recent studies point to aberrant mitophagy in ocular neurodegenerative disorders which could be an important contributor to the disease etiology/pathology. This review article highlights some of the recent findings that point to dysregulation of mitophagy and it's underlying mechanisms in ocular neurodegenerative diseases, including, glaucoma, age-related macular degeneration and diabetic retinopathy.
    Keywords:  age-related macular degeneration; diabetic retinopathy; glaucoma; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fnins.2023.1299552
  5. Int J Mol Sci. 2023 Nov 02. pii: 15919. [Epub ahead of print]24(21):
    PHB2 Alleviates Neurotoxicity of Prion Peptide PrP106-126 via PINK1/Parkin-Dependent Mitophagy.
    Xiaohui Zheng, Kun Liu, Qingqing Xie, Hangkuo Xin, Wei Chen, Shengyu Lin, Danqi Feng, Ting Zhu.
      Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy that clears injured mitochondria. Prohibitin 2 (PHB2) has been identified as a novel inner membrane mitophagy receptor that mediates mitophagy. However, the role of PHB2 in prion diseases remains unclear. In this study, we isolated primary cortical neurons from rats and used the neurotoxic prion peptide PrP106-126 as a cell model for prion diseases. We examined the role of PHB2 in PrP106-126-induced mitophagy using Western blotting and immunofluorescence microscopy and assessed the function of PHB2 in PrP106-126-induced neuronal death using the cell viability assay and the TUNEL assay. The results showed that PrP106-126 induced mitochondrial morphological abnormalities and mitophagy in primary cortical neurons. PHB2 was found to be indispensable for PrP106-126-induced mitophagy and was involved in the accumulation of PINK1 and recruitment of Parkin to mitochondria in primary neurons. Additionally, PHB2 depletion exacerbated neuronal cell death induced by PrP106-126, whereas the overexpression of PHB2 alleviated PrP106-126 neuronal toxicity. Taken together, this study demonstrated that PHB2 is indispensable for PINK1/Parkin-mediated mitophagy in PrP106-126-treated neurons and protects neurons against the neurotoxicity of the prion peptide.
    Keywords:  PHB2; PINK1/Parkin; PrP106–126; mitophagy; neuronal death; prion disease; prion peptide
    DOI:  https://doi.org/10.3390/ijms242115919
  6. Cell Death Dis. 2023 11 11. 14(11): 736
    FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment.
    Xingzong Sun, Menghan Qian, Hongliang Li, Lei Wang, Yunjie Zhao, Min Yin, Lili Dai, Hongkun Bao.
      Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS) that is characterized by myelin damage, followed by axonal and ultimately neuronal loss, which has been found to be associated with mitophagy. The etiology and pathology of MS remain elusive. However, the role of FK506 binding protein 5 (FKBP5, also called FKBP51), a newly identified gene associated with MS, in the progression of the disease has not been well defined. Here, we observed that the progress of myelin loss and regeneration in Fkbp5ko mice treated with demyelination for the same amount of time was significantly slower than that in wild-type mice, and that mitophagy plays an important regulatory role in this process. To investigate the mechanism, we discovered that the levels of FKBP5 protein were greatly enhanced in the CNS of cuprizone (CPZ) mice and the myelin-denuded environment stimulates significant activation of the PINK1/Parkin-mediated mitophagy, in which the important regulator, PPAR-γ, is critically regulated by FKBP5. This study reveals the role of FKBP5 in regulating a dynamic pathway of natural restorative regulation of mitophagy through PPAR-γ in pathological demyelinating settings, which may provide potential targets for the treatment of demyelinating diseases.
    DOI:  https://doi.org/10.1038/s41419-023-06260-7
  7. Nat Aging. 2023 Nov 13.
    A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan.
    Manish Chamoli, Anand Rane, Anna Foulger, Shankar J Chinta, Azar Asadi Shahmirzadi, Caroline Kumsta, Dhanya K Nambiar, David Hall, Angelina Holcom, Suzanne Angeli, Minna Schmidt, Sharon Pitteri, Malene Hansen, Gordon J Lithgow, Julie K Andersen.
      Autophagy-lysosomal function is crucial for maintaining healthy lifespan and preventing age-related diseases. The transcription factor TFEB plays a key role in regulating this pathway. Decreased TFEB expression is associated with various age-related disorders, making it a promising therapeutic target. In this study, we screened a natural product library and discovered mitophagy-inducing coumarin (MIC), a benzocoumarin compound that enhances TFEB expression and lysosomal function. MIC robustly increases the lifespan of Caenorhabditis elegans in an HLH-30/TFEB-dependent and mitophagy-dependent manner involving DCT-1/BNIP3 while also preventing mitochondrial dysfunction in mammalian cells. Mechanistically, MIC acts by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12/FXR, which, in turn, induces mitophagy and extends lifespan. In conclusion, our study uncovers MIC as a promising drug-like molecule that enhances mitochondrial function and extends lifespan by targeting DAF-12/FXR. Furthermore, we discovered DAF-12/FXR as a previously unknown upstream regulator of HLH-30/TFEB and mitophagy.
    DOI:  https://doi.org/10.1038/s43587-023-00524-9
  8. Mol Neurodegener. 2023 Nov 11. 18(1): 83
    Mitochondrial dysfunction in Parkinson's disease - a key disease hallmark with therapeutic potential.
    Martin T Henrich, Wolfgang H Oertel, D James Surmeier, Fanni F Geibl.
      Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson's disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment of electron transport chain complex 1, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and cellular bioenergetic deficiency. In addition, we outline mitochondrial pathways to neurodegeneration in the current context of PD pathogenesis, and review past and current treatment strategies in an attempt to better understand why translational efforts thus far have been unsuccessful.
    Keywords:  Antioxidants; Electron transport chain; MPTP; Mitochondria; Mitochondrial dysfunction; Neuroprotective therapies; Parkinson’s disease; Synuclein
    DOI:  https://doi.org/10.1186/s13024-023-00676-7
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