bims-mitpro 2024-06-30 papers

bims-mitpro

Biomed News

on Mitochondrial proteostasis

Issue of 2024–06–30
six papers selected by
Andreas Kohler, Umeå University

Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice.
ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.
Simple prerequisite of presequence for mitochondrial protein import in the unicellular red alga Cyanidioschyzon merolae.
Defective mitochondria-lysosomal axis enhances the release of extracellular vesicles containing mitochondrial DNA and proteins in Huntington's disease.
Advancements in unravelling the fundamental function of the ATAD3 protein in multicellular organisms.
The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis.

Int J Mol Sci. 2024 Jun 11. pii: 6441. [Epub ahead of print]25(12):

Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice.

Andrew J Trease, Steven Totusek, Eliezer Z Lichter, Kelly L Stauch, Howard S Fox.

  Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function.

Keywords:  Parkin; Parkinson’s disease; aging; metabolism; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/ijms25126441
Stroke. 2024 Jul;55(7): 1904-1913

ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.

Hong An, Bing Zhou, Kazuhide Hayakawa, Violeta Durán Laforet, Ji-Hyun Park, Yoshihiko Nakamura, Emiri T Mandeville, Ning Liu, Shuzhen Guo, Zhanyang Yu, Jingfei Shi, Di Wu, Wenlu Li, Eng H Lo, Xunming Ji.

   BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke.
METHODS: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.
RESULTS: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes.
CONCLUSIONS: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.

Keywords:  homeostasis; ischemic stroke; meclizine; oligomycins; unfolded protein response

DOI:  https://doi.org/10.1161/STROKEAHA.123.045550
J Cell Sci. 2024 Jun 28. pii: jcs.262042. [Epub ahead of print]

Simple prerequisite of presequence for mitochondrial protein import in the unicellular red alga Cyanidioschyzon merolae.

Riko Hirata, Yuko Mogi, Kohei Takahashi, Hisayoshi Nozaki, Tetsuya Higashiyama, Yamato Yoshida.

  Mitochondrial biogenesis relies on hundreds of proteins that are derived from genes encoded in the nucleus. According to characteristic properties of N-terminal targeting peptides (TP) and multi-step authentication by the protein translocase called the TOM complex, nascent polypeptides satisfying the requirements are imported into mitochondria. However, it is unknown whether eukaryotic cells with a single mitochondrion per cell have a similar complexity of presequence requirements for mitochondrial protein import compared to other eukaryotes with multiple mitochondria. Based on putative mitochondrial TP sequences in the unicellular red alga Cyanidioschyzon merolae, we designed synthetic TPs (synTPs) and showed that functional TPs must have at least one basic residue and a specific amino acid composition, although their physicochemical properties are not strictly determined. Combined with the simple composition of the TOM complex in C. merolae, our results suggest that a regional positive charge in TP is verified solely by TOM22 for mitochondrial protein import in C. merolae. The simple authentication mechanism indicates that the monomitochondrial C. merolae does not need to increase the cryptographic complexity of the lock-and-key mechanism for mitochondrial protein import.

Keywords:  Mitochondrial presequence; Mitochondrial protein import; Monomitochondrial eukaryote; Unicellular red alga

DOI:  https://doi.org/10.1242/jcs.262042
J Extracell Biol. 2022 Oct;1(10): e65

Defective mitochondria-lysosomal axis enhances the release of extracellular vesicles containing mitochondrial DNA and proteins in Huntington's disease.

Margarida Beatriz, Rita Vilaça, Sandra I Anjo, Bruno Manadas, Cristina Januário, A Cristina Rego, Carla Lopes.

  Mitochondrial and autophagy dysfunction are mechanisms proposed to be involved in the pathogenesis of several neurodegenerative diseases. Huntington's disease (HD) is a progressive neurodegenerative disorder associated with mutant Huntingtin-induced abnormalities in neuronal mitochondrial dynamics and quality control. Former studies suggest that the removal of defective mitochondria may be compromised in HD. Mitochondrial quality control (MQC) is a complex, well-orchestrated pathway that can be compromised through mitophagy dysregulation or impairment in the mitochondria-lysosomal axis. Another mitochondrial stress response is the generation of mitochondrial-derived vesicles that fuse with the endolysosomal system and form multivesicular bodies that are extruded from cells as extracellular vesicles (EVs). In this work, we aimed to study the presence of mitochondrial components in human EVs and the relation to the dysfunction of both mitochondria and the autophagy pathway. We comprehensively characterized the mitochondrial and autophagy alterations in premanifest and manifest HD carriers and performed a proteomic and genomic EVs profile. We observed that manifest HD patients exhibit mitochondrial and autophagy impairment associated with enhanced EVs release. Furthermore, we detected mitochondrial DNA and proteins in EVs released by HD cells and in neuronal-derived EVs including VDAC-1 and alpha and beta subunits of ATP synthase F1. HD-extracellular vesicles transport higher levels of mitochondrial genetic material in manifest HD patients, suggesting an alternative pathway for the secretion of reactive mitochondrial components. This study provides a novel framework connecting EVs enhanced release of mitochondrial components to mitochondrial and lysosomal dysfunction in HD.

Keywords:  Huntington's disease; autophagy; extracellular vesicles; mitochondrial DNA; mitochondrial dysfunction; neuronal‐derived extracellular vesicles

DOI:  https://doi.org/10.1002/jex2.65
Adv Biol Regul. 2024 Jun 18. pii: S2212-4926(24)00029-0. [Epub ahead of print]93 101041

Advancements in unravelling the fundamental function of the ATAD3 protein in multicellular organisms.

Divya Goel, Sudhir Kumar.

  ATPase family AAA domain containing protein 3, commonly known as ATAD3 is a versatile mitochondrial protein that is involved in a large number of pathways. ATAD3 is a transmembrane protein that spans both the inner mitochondrial membrane and outer mitochondrial membrane. It, therefore, functions as a connecting link between the mitochondrial lumen and endoplasmic reticulum facilitating their cross-talk. ATAD3 contains an N-terminal domain which is amphipathic in nature and is inserted into the membranous space of the mitochondria, while the C-terminal domain is present towards the lumen of the mitochondria and contains the ATPase domain. ATAD3 is known to be involved in mitochondrial biogenesis, cholesterol transport, hormone synthesis, apoptosis and several other pathways. It has also been implicated to be involved in cancer and many neurological disorders making it an interesting target for extensive studies. This review aims to provide an updated comprehensive account of the role of ATAD3 in the mitochondria especially in lipid transport, mitochondrial-endoplasmic reticulum interactions, cancer and inhibition of mitophagy.

Keywords:  AAA domain containing protein; ATAD3; Cancer; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.jbior.2024.101041
RNA Biol. 2024 Jan;21(1): 23-30

The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis.

Christian D Mutti, Lindsey Van Haute, Michal Minczuk.

  Ribosomes are large macromolecular complexes composed of both proteins and RNA, that require a plethora of factors and post-transcriptional modifications for their biogenesis. In human mitochondria, the ribosomal RNA is post-transcriptionally modified at ten sites. The N4-methylcytidine (m4C) methyltransferase, METTL15, modifies the 12S rRNA of the small subunit at position C1486. The enzyme is essential for mitochondrial protein synthesis and assembly of the mitoribosome small subunit, as shown here and by previous studies. Here, we demonstrate that the m4C modification is not required for small subunit biogenesis, indicating that the chaperone-like activity of the METTL15 protein itself is an essential component for mitoribosome biogenesis.

Keywords:  Mitochondrial ribosome; chaperone; epitranscriptomics; methyltransferase; mitochondria; ribosomal RNA

DOI:  https://doi.org/10.1080/15476286.2024.2369374