bims-mitpro 2023-11-19 papers

bims-mitpro

Biomed News

on Mitochondrial proteostasis

Issue of 2023–11–19
ten papers selected by
Andreas Kohler, Umeå University

Mitochondrial entry gate as regulatory hub.
Study of ATF4/CHOP axis-mediated mitochondrial unfolded protein response in neuronal apoptosis induced by methylmercury.
Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation.
GTPBP8 is required for mitoribosomal biogenesis and mitochondrial translation.
Role of mitophagy in ocular neurodegeneration.
Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.
PHB2 Alleviates Neurotoxicity of Prion Peptide PrP106-126 via PINK1/Parkin-Dependent Mitophagy.
Mitochondrial dysfunction in Parkinson's disease - a key disease hallmark with therapeutic potential.
FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment.
FOXO1 reduces STAT3 activation and causes impaired mitochondrial quality control in diabetic cardiomyopathy.

Biochim Biophys Acta Mol Cell Res. 2023 Jul 04. pii: S0167-4889(23)00101-5. [Epub ahead of print] 119529

Mitochondrial entry gate as regulatory hub.

Fabian den Brave, Nikolaus Pfanner, Thomas Becker.

  Mitochondria import 1000-1300 different precursor proteins from the cytosol. The main mitochondrial entry gate is formed by the translocase of the outer membrane (TOM complex). Molecular coupling and modification of TOM subunits control and modulate protein import in response to cellular signaling. The TOM complex functions as regulatory hub to integrate mitochondrial protein biogenesis and quality control into the cellular proteostasis network.

Keywords:  Mitochondria; Protein sorting; Proteostasis; Quality control; Stress response; TOM complex

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119529
Food Chem Toxicol. 2023 Nov 13. pii: S0278-6915(23)00592-6. [Epub ahead of print] 114190

Study of ATF4/CHOP axis-mediated mitochondrial unfolded protein response in neuronal apoptosis induced by methylmercury.

Si Xu, Haihui Liu, Chen Wang, Yu Deng, Bin Xu, Tianyao Yang, Wei Liu.

  Methylmercury (MeHg) is a widely distributed environmental pollutant that can easily cross the blood-brain barrier and accumulate in the brain, thereby damaging the central nervous system. Studies have shown that MeHg-induced mitochondrial damage and apoptosis play a crucial role in its neurotoxic effects. Mitochondrial unfolded protein response (UPRmt) is indispensable to maintain mitochondrial protein homeostasis and ensure mitochondrial function, and the ATF4/CHOP axis is one of the signaling pathways to activate UPRmt. In this study, the role of the ATF4/CHOP axis-mediated UPRmt in the neurotoxicity of MeHg has been investigated by C57BL/6 mice and the HT22 cell line. We discovered that mice exposed to MeHg had abnormal neurobehavioral patterns. The pathological section showed a significant decrease in the number of neurons. MeHg also resulted in a reduction in mtDNA copy number and mitochondrial membrane potential (MMP). Additionally, the ATF4/CHOP axis and UPRmt were found to be significantly activated. Subsequently, we used siRNA to knock down ATF4 or CHOP and observed that the expression of UPRmt-related proteins and the apoptosis rate were significantly reduced. Our research showed that exposure to MeHg can over-activate the UPRmt through the ATF4/CHOP axis, leading to mitochondrial damage and ultimately inducing neuronal apoptosis.

Keywords:  ATF4; Apoptosis; CHOP; Methylmercury; Neurotoxicity; UPR(mt)

DOI:  https://doi.org/10.1016/j.fct.2023.114190
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
Cell Mol Life Sci. 2023 Nov 16. 80(12): 361

GTPBP8 is required for mitoribosomal biogenesis and mitochondrial translation.

Liang Wang, Taru Hilander, Xiaonan Liu, Hoi Ying Tsang, Ove Eriksson, Christopher B Jackson, Markku Varjosalo, Hongxia Zhao.

  Mitochondrial translation occurs on the mitochondrial ribosome, also known as the mitoribosome. The assembly of mitoribosomes is a highly coordinated process. During mitoribosome biogenesis, various assembly factors transiently associate with the nascent ribosome, facilitating the accurate and efficient construction of the mitoribosome. However, the specific factors involved in the assembly process, the precise mechanisms, and the cellular compartments involved in this vital process are not yet fully understood. In this study, we discovered a crucial role for GTP-binding protein 8 (GTPBP8) in the assembly of the mitoribosomal large subunit (mt-LSU) and mitochondrial translation. GTPBP8 is identified as a novel GTPase located in the matrix and peripherally bound to the inner mitochondrial membrane. Importantly, GTPBP8 is specifically associated with the mt-LSU during its assembly. Depletion of GTPBP8 leads to an abnormal accumulation of mt-LSU, indicating that GTPBP8 is critical for proper mt-LSU assembly. Furthermore, the absence of GTPBP8 results in reduced levels of fully assembled 55S monosomes. This impaired assembly leads to compromised mitochondrial translation and, consequently, impaired mitochondrial function. The identification of GTPBP8 as an important player in these processes provides new insights into the molecular mechanisms underlying mitochondrial protein synthesis and its regulation.

Keywords:  GTP binding protein; Mitochondria; Mitochondrial translation; Mitoribosomal protein; Mitoribosome; Mitoribosome assembly; Mitoribosome large subunit

DOI:  https://doi.org/10.1007/s00018-023-05014-0
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
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
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
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
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
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