bims-mitpro Biomed News
on Mitochondrial proteostasis
Issue of 2025–01–12
seven papers selected by
Andreas Kohler, Umeå University
  1. Mitochondrial YME1L1 governs unoccupied protein translocase channels.
  2. Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex.
  3. Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.
  4. Mitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?
  5. Triacylglycerol mobilization underpins mitochondrial stress recovery.
  6. COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
  7. TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.
  1. Nat Cell Biol. 2025 Jan 07.
    Mitochondrial YME1L1 governs unoccupied protein translocase channels.
    Meng-Chieh Hsu, Hiroki Kinefuchi, Linlin Lei, Reika Kikuchi, Koji Yamano, Richard J Youle.
      Mitochondrial protein import through the outer and inner membranes is key to mitochondrial biogenesis. Recent studies have explored how cells respond when import is impaired by a variety of different insults. Here, we developed a mammalian import blocking system using dihydrofolate reductase fused to the N terminus of the inner membrane protein MIC60. While stabilization of the dihydrofolate reductase domain by methotrexate inhibited endogenous mitochondrial protein import, it neither activated the transcription factor ATF4, nor was affected by ATAD1 expression or by VCP/p97 inhibition. On the other hand, notably, plugging the channel of translocase of the outer membrane) induced YME1L1, an ATP-dependent protease, to eliminate translocase of the inner membrane (TIM23) channel components TIMM17A and TIMM23. The data suggest that unoccupied TIM23 complexes expose a C-terminal degron on TIMM17A to YME1L1 for degradation. Import plugging caused a cell growth defect and loss of YME1L1 exacerbated the growth inhibition, showing the protective effect of YME1L1 activity. YME1L1 seems to play a crucial role in mitochondrial quality control to counteract precursor stalling in the translocase of the outer membrane complex and unoccupied TIM23 channels.
    DOI:  https://doi.org/10.1038/s41556-024-01571-z
  2. Genes (Basel). 2024 Nov 28. pii: 1534. [Epub ahead of print]15(12):
    Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex.
    Sahil Jain, Eyal Paz, Abdussalam Azem.
      The human mitochondrial proteome comprises approximately 1500 proteins, with only 13 being encoded by mitochondrial DNA. The remainder are encoded by the nuclear genome, translated by cytosolic ribosomes, and subsequently imported into and sorted within mitochondria. The process of mitochondria-destined protein import is mediated by several intricate protein complexes distributed among the four mitochondrial compartments. The focus of this mini-review is the translocase of the inner membrane 23 (TIM23) complex that assists in the import of ~60% of the mitochondrial proteome, which includes the majority of matrix proteins as well as some inner membrane and intermembrane space proteins. To date, numerous pathogenic mutations have been reported in the genes encoding various components of the TIM23 complex. These diseases exhibit mostly developmental and neurological defects at an early age. Interestingly, accumulating evidence supports the possibility that the gene for Tim50 represents a hotspot for disease-causing mutations among core TIM23 complex components, while genes for the mitochondrial Hsp70 protein (mortalin) and its J domain regulators represent hotspots for mutations affecting presequence translocase-associated motor (PAM) subunits. The potential mechanistic implications of the discovery of disease-causing mutations on the function of the TIM23 complex, in particular Tim50, are discussed.
    Keywords:  TIM23 complex; Timm50; mitochondrial protein import; rare genetic disorders
    DOI:  https://doi.org/10.3390/genes15121534
  3. Biomolecules. 2024 Dec 22. pii: 1649. [Epub ahead of print]14(12):
    Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.
    Lydia Shen, Ulf Dettmer.
      The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson's disease (PD), a brain disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Consequently, impaired mitochondrial quality control may play a key role in PD pathology. This is affirmed by work indicating that genes such as PRKN and PINK1, which participate in multiple mitochondrial processes, harbor PD-associated mutations. Furthermore, mitochondrial complex-I-inhibiting toxins like MPTP and rotenone are known to cause Parkinson-like symptoms. At the heart of PD is alpha-synuclein (αS), a small synaptic protein that misfolds and aggregates to form the disease's hallmark Lewy bodies. The specific mechanisms through which aggregated αS exerts its neurotoxicity are still unknown; however, given the vital role of both αS and mitochondria to PD, an understanding of how αS influences mitochondrial maintenance may be essential to elucidating PD pathogenesis and discovering future therapeutic targets. Here, the current knowledge of the relationship between αS and mitochondrial quality control pathways in PD is reviewed, highlighting recent findings regarding αS effects on mitochondrial biogenesis, dynamics, and autophagy.
    Keywords:  PGC-1α; PINK1/Parkin; Parkinson’s disease; mitochondrial dysfunction; mitochondrial fragmentation; mitophagy; α-synuclein
    DOI:  https://doi.org/10.3390/biom14121649
  4. Biochemistry. 2025 Jan 04.
    Mitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?
    Roshika Ravi, Deepsikha Routray, Radhakrishnan Mahalakshmi.
      The mitochondrial outer membrane (OMM) β-barrel proteins link the mitochondrion with the cytosol, endoplasmic reticulum, and other cellular membranes, establishing cellular homeostasis. Their active insertion and assembly in the outer mitochondrial membrane is achieved in an energy-independent yet highly effective manner by the Sorting and Assembly Machinery (SAM) of the OMM. The core SAM constituent is the 16-stranded transmembrane β-barrel Sam50. For over two decades, the primary role of Sam50 has been linked to its function as a chaperone in the OMM, wherein it assembles all β-barrels through a lateral gating and β-barrel switching mechanism. Interestingly, recent studies have demonstrated that despite its low copy number, Sam50 performs various diverse functions beyond assembling β-barrels. This includes maintaining cristae morphology, bidirectional lipid shuttling between the ER and mitochondrial inner membrane, import of select proteins, regulation of PINK1-Parkin function, and timed trigger of cell death. Given these multifaceted critical regulatory functions of SAM across all eukaryotes, we now reason that SAM merely moonlights as the hub for β-barrel biogenesis and has indeed evolved a diverse array of primary roles in maintaining mitochondrial function and cellular homeostasis.
    Keywords:  MERCS; Sam50; barrel biogenesis; lipid transport; membrane protein folding; mitochondrial chaperone
    DOI:  https://doi.org/10.1021/acs.biochem.4c00727
  5. Nat Cell Biol. 2025 Jan 08.
    Triacylglycerol mobilization underpins mitochondrial stress recovery.
    Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.
      Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01586-6
  6. Life Sci Alliance. 2025 Mar;pii: e202403013. [Epub ahead of print]8(3):
    COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
    Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie S Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor.
      Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.
    DOI:  https://doi.org/10.26508/lsa.202403013
  7. Genes Dis. 2025 Mar;12(2): 101429
    TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.
    Xin He, Mulan Chen, Yepeng Fan, Bin Wu, Zhifang Dong.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.
    Keywords:  Autophagy; Mitochondrial biogenesis; Mitophagy; Parkinson's disease; TFE3; α-synuclein
    DOI:  https://doi.org/10.1016/j.gendis.2024.101429
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