bims-mitdyn 2023-07-30 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2023‒07‒30
eleven papers selected by
Edmond Chan
Queen’s University, School of Medicine

Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.
PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics.
COPI-regulated mitochondria-ER contact site formation maintains axonal integrity.
Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes.
UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.
Hyper-ubiquitylation of DNA helicase RECQL4 by E3 ligase MITOL prevents mitochondrial entry and potentiates mitophagy.
Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in the PARL deficient mouse model of Leigh Syndrome.
Promotion of mitochondrial fragmentation suppresses the formation of mitochondrial spherical compartmentation in PINK1B9Drosophila melanogaster.
The Role of Mitochondrial Dynamics and Mitotic Fission in Regulating the Cell Cycle in Cancer and Pulmonary Arterial Hypertension: Implications for Dynamin-Related Protein 1 and Mitofusin2 in Hyperproliferative Diseases.
Hotly awaited structures obtained for the human protein UCP1.
ZDHHC21: a mitochondrial vulnerability in AML.

Proc Natl Acad Sci U S A. 2023 08;120(31): e2300475120

Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.

Qingqing Liu, Benjamin Fong, Seungmin Yoo, Jay R Unruh, Fengli Guo, Zulin Yu, Jingjing Chen, Kausik Si, Rong Li, Chuankai Zhou.

  Eukaryotes organize cellular contents into membrane-bound organelles and membrane-less condensates, for example, protein aggregates. An unsolved question is why the ubiquitously distributed proteins throughout the cytosol give rise to spatially localized protein aggregates on the organellar surface, like mitochondria. We report that the mitochondrial import receptor Tom70 is involved in the localized condensation of protein aggregates in budding yeast and human cells. This is because misfolded cytosolic proteins do not autonomously aggregate in vivo; instead, they are recruited to the condensation sites initiated by Tom70's substrates (nascent mitochondrial proteins) on the organellar membrane using multivalent hydrophobic interactions. Knocking out Tom70 partially impairs, while overexpressing Tom70 increases the formation and association between cytosolic protein aggregates and mitochondria. In addition, ectopic targeting Tom70 and its substrates to the vacuole surface is able to redirect the localized aggregation from mitochondria to the vacuolar surface. Although other redundant mechanisms may exist, this nascent mitochondrial proteins-based initiation of protein aggregation likely explains the localized condensation of otherwise ubiquitously distributed molecules on the mitochondria. Disrupting the mitochondrial association of aggregates impairs their asymmetric retention during mitosis and reduces the mitochondrial import of misfolded proteins, suggesting a proteostasis role of the organelle-condensate interactions.

Keywords:  condensate; mitochondria; protein aggregation

DOI:  https://doi.org/10.1073/pnas.2300475120
Cell Rep. 2023 Jul 26. pii: S2211-1247(23)00906-3. [Epub ahead of print]42(8): 112895

PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics.

Sudeshna Nag, Kaitlin Szederkenyi, Olena Gorbenko, Hannah Tyrrell, Christopher M Yip, G Angus McQuibban.

  Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and dynamin-related protein 1 (DRP1). Mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) is emerging as a regulator of these post-translational modifications; however, its precise role in the regulation of mitochondrial morphology is unknown. We show that PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner. PGAM5 regulates MFN2 phosphorylation and consequently protects it from ubiquitination and degradation. Further, phosphorylation and dephosphorylation modification of MFN2 regulates its fusion ability. Phosphorylation enhances fission and degradation, whereas dephosphorylation enhances fusion. PGAM5 dephosphorylates MFN2 to promote mitochondrial network formation. Further, using a Drosophila genetic model, we demonstrate that the MFN2 homolog Marf and dPGAM5 are in the same biological pathway. Our results identify MFN2 dephosphorylation as a regulator of mitochondrial fusion and PGAM5 as an MFN2 phosphatase.

Keywords:  CP: Molecular biology; DRP1; MFN2; PGAM5; mitochondrial morphology

DOI:  https://doi.org/10.1016/j.celrep.2023.112895
Cell Rep. 2023 Jul 26. pii: S2211-1247(23)00894-X. [Epub ahead of print]42(8): 112883

COPI-regulated mitochondria-ER contact site formation maintains axonal integrity.

Daniel C Maddison, Bilal Malik, Leonardo Amadio, Dana M Bis-Brewer, Stephan Züchner, Owen M Peters, Gaynor A Smith.

  Coat protein complex I (COPI) is best known for its role in Golgi-endoplasmic reticulum (ER) trafficking, responsible for the retrograde transport of ER-resident proteins. The ER is crucial to neuronal function, regulating Ca2+ homeostasis and the distribution and function of other organelles such as endosomes, peroxisomes, and mitochondria via functional contact sites. Here we demonstrate that disruption of COPI results in mitochondrial dysfunction in Drosophila axons and human cells. The ER network is also disrupted, and the neurons undergo rapid degeneration. We demonstrate that mitochondria-ER contact sites (MERCS) are decreased in COPI-deficient axons, leading to Ca2+ dysregulation, heightened mitophagy, and a decrease in respiratory capacity. Reintroducing MERCS is sufficient to rescue not only mitochondrial distribution and Ca2+ uptake but also ER morphology, dramatically delaying neurodegeneration. This work demonstrates an important role for COPI-mediated trafficking in MERC formation, which is an essential process for maintaining axonal integrity.

Keywords:  Axon transport; COPI; CP: Cell biology; Calcium homeostasis; Endoplasmic reticulum; Golgi; Mitochondria; Neuronal cell biology; Vesicle trafficking

DOI:  https://doi.org/10.1016/j.celrep.2023.112883
Elife. 2023 Jul 25. pii: e85878. [Epub ahead of print]12

Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes.

Liang Ma, Jasleen Singh, Randy Schekman.

  Fusion of multivesicular bodies (MVBs) with the plasma membrane results in the secretion of intraluminal vesicles (ILVs), or exosomes. The sorting of one exosomal cargo RNA, miR223, is facilitated by the RNA-binding protein, YBX1 (Shurtleff et al., 2016). We found that miR223 specifically binds a 'cold shock' domain (CSD) of YBX1 through a 5' proximal sequence motif UCAGU that may represent a binding site or structural feature required for sorting. Prior to sorting into exosomes, most of the cytoplasmic miR223 resides in mitochondria. An RNA-binding protein localized to the mitochondrial matrix, YBAP1, appears to serve as a negative regulator of miR223 enrichment into exosomes. miR223 levels decreased in the mitochondria and increased in exosomes after loss of YBAP1. We observed YBX1 shuttle between mitochondria and endosomes in live cells. YBX1 also partitions into P body granules in the cytoplasm (Liu et al., 2021). We propose a model in which miR223 and likely other miRNAs are stored in mitochondria and are then mobilized by YBX1 to cytoplasmic phase condensate granules for capture into invaginations in the endosome that give rise to exosomes.

Keywords:  cell biology; human

DOI:  https://doi.org/10.7554/eLife.85878
EMBO Rep. 2023 Jul 28. e55859

UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.

Qilian Ma, Jiaqi Xin, Qiang Peng, Ningning Li, Shan Sun, Hongyu Hou, Guoqiang Ma, Nana Wang, Li Zhang, Kin Yip Tam, Heiko Dussmann, Jochen Hm Prehn, Hongfeng Wang, Zheng Ying.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging-related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin-dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin-mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.

Keywords:  ALS; Parkin; UBQLN2; mitophagy; ubiquitin

DOI:  https://doi.org/10.15252/embr.202255859
J Biol Chem. 2023 Jul 24. pii: S0021-9258(23)02115-4. [Epub ahead of print] 105087

Hyper-ubiquitylation of DNA helicase RECQL4 by E3 ligase MITOL prevents mitochondrial entry and potentiates mitophagy.

Mansoor Hussain, Aftab Mohammed, Shabnam Saifi, Swati Priya, Sagar Sengupta.

  Mutations in the DNA helicase RECQL4 lead to Rothmund-Thomson Syndrome (RTS), a disorder characterized by mitochondrial dysfunctions, premature aging, and genomic instability. However, the mechanisms by which these mutations lead to pathology are unclear. Here we report that RECQL4 is ubiquitylated by a mitochondrial E3 ligase, MITOL, at two lysine residues (K1101, K1154) via K6 linkage. This ubiquitylation hampers the interaction of RECQL4 with mitochondrial importer Tom20, thereby restricting its own entry into mitochondria. We show the RECQL4 2K mutant (where both K1101 and K1154 are mutated) has increased entry into mitochondria and demonstrates enhanced mtDNA replication. We observed that the three tested RTS patient mutants were unable to enter the mitochondria and showed decreased mtDNA replication. Furthermore, we found that RECQL4 in RTS patient mutants are hyper-ubiquitylated by MITOL and form insoluble aggregate-like structures on the outer mitochondrial surface. However, depletion of MITOL allows RECQL4 expressed in these RTS mutants to enter mitochondria and rescue mtDNA replication. Finally, we show increased accumulation of hyper-ubiquitylated RECQL4 outside the mitochondria leads to the cells being potentiated to increased mitophagy. Hence, we conclude regulating the turnover of RECQL4 by MITOL may have a therapeutic effect in RTS patients.

Keywords:  E3 ligases; RecQ helicases; Rothmund Thomson Syndrome; autophagy; mitochondrial replication

DOI:  https://doi.org/10.1016/j.jbc.2023.105087
Elife. 2023 Jul 28. pii: e84710. [Epub ahead of print]12

Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in the PARL deficient mouse model of Leigh Syndrome.

Enrico Radaelli, Charles-Antoine Assenmacher, Jillian Verrelle, Esha Banerjee, Florence Manero, Salim Khiati, Anais Girona, Guillermo Lopez-Lluch, Placido Navas, Marco Spinazzi.

  Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis at meiotic prophase I, followed by germ cell death independently of neurodegeneration. Genetic modifications of PINK1, PGAM5, and TTC19, three major substrates of PARL with important roles in mitochondrial homeostasis, do not reproduce or modify this severe phenotype. PARL deficiency in spermatocytes leads to severe abnormalities in mitochondrial structure associated with prominent electron transfer chain defects, alterations in Coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ-cell specific decrease in GPX4 expression committing arrested spermatocytes to ferroptosis, a regulated cell death modality characterized by uncontrolled lipid peroxidation. Thus, mitochondrial defects, such as those induced by depletion of PARL, spontaneously initiate ferroptosis in primary spermatocytes in vivo by simultaneous effects on GPX4 and CoQ, the two major ferroptosis-inhibitors. Ferroptosis warrants to be further scrutinized in the pathogenesis of mitochondrial diseases and male infertility.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.84710
Biochem Biophys Res Commun. 2023 Jul 14. pii: S0006-291X(23)00879-3. [Epub ahead of print]676 48-57

Promotion of mitochondrial fragmentation suppresses the formation of mitochondrial spherical compartmentation in PINK1B9Drosophila melanogaster.

Yi Li, Wen Chen, Danling Wang.

  Mitochondria undergo structural changes reflective of functional statuses. Ultrastructural characterizing of mitochondria is valuable for understanding mitochondrial dysfunction in various pathological conditions. PINK1, a Parkinson's disease (PD) associated gene, plays key roles in maintaining mitochondrial function and integrity. In Drosophila melanogaster, deficiency of PINK1 results in PD-like pathologies due to mitochondrial abnormalities. Here, we report the existence of a new type of mitochondrial-membrane deformity, mitochondrial spherical compartmentation (MSC), caused by PINK1 deficiency in Drosophila. The MSC is a three-dimensional spheroid-like mitochondrial membrane structure encompassing nonselective contents. Upregulation of dDrp1, downregulation of dMarf, and upregulation of dArgK1-A-all resulting in mitochondrial fragmentation-were able to suppress the formation of MSC. Furthermore, arginine kinase, only when localizing to the vicinity of mitochondria, induced mitochondrial fragmentation and reversed the MSC phenotype. In summary, this study demonstrates that loss of dPINK1 leads to the formation of mitochondrial-membrane deformity MSC, which responds to mitochondrial dynamics. In addition, our data suggest a new perspective of how phosphagen energy-buffer system might regulate mitochondrial dynamics.

Keywords:  Arginine kinase; Mitochondrial spherical compartmentation; Mitochondrial-membrane deformity; PINK1; Transmission electron microscopy

DOI:  https://doi.org/10.1016/j.bbrc.2023.07.022
Cells. 2023 Jul 20. pii: 1897. [Epub ahead of print]12(14):

The Role of Mitochondrial Dynamics and Mitotic Fission in Regulating the Cell Cycle in Cancer and Pulmonary Arterial Hypertension: Implications for Dynamin-Related Protein 1 and Mitofusin2 in Hyperproliferative Diseases.

Pierce Colpman, Asish Dasgupta, Stephen L Archer.

  Mitochondria, which generate ATP through aerobic respiration, also have important noncanonical functions. Mitochondria are dynamic organelles, that engage in fission (division), fusion (joining) and translocation. They also regulate intracellular calcium homeostasis, serve as oxygen-sensors, regulate inflammation, participate in cellular and organellar quality control and regulate the cell cycle. Mitochondrial fission is mediated by the large GTPase, dynamin-related protein 1 (Drp1) which, when activated, translocates to the outer mitochondrial membrane (OMM) where it interacts with binding proteins (Fis1, MFF, MiD49 and MiD51). At a site demarcated by the endoplasmic reticulum, fission proteins create a macromolecular ring that divides the organelle. The functional consequence of fission is contextual. Physiological fission in healthy, nonproliferating cells mediates organellar quality control, eliminating dysfunctional portions of the mitochondria via mitophagy. Pathological fission in somatic cells generates reactive oxygen species and triggers cell death. In dividing cells, Drp1-mediated mitotic fission is critical to cell cycle progression, ensuring that daughter cells receive equitable distribution of mitochondria. Mitochondrial fusion is regulated by the large GTPases mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2), which fuse the OMM, and optic atrophy 1 (OPA-1), which fuses the inner mitochondrial membrane. Mitochondrial fusion mediates complementation, an important mitochondrial quality control mechanism. Fusion also favors oxidative metabolism, intracellular calcium homeostasis and inhibits cell proliferation. Mitochondrial lipids, cardiolipin and phosphatidic acid, also regulate fission and fusion, respectively. Here we review the role of mitochondrial dynamics in health and disease and discuss emerging concepts in the field, such as the role of central versus peripheral fission and the potential role of dynamin 2 (DNM2) as a fission mediator. In hyperproliferative diseases, such as pulmonary arterial hypertension and cancer, Drp1 and its binding partners are upregulated and activated, positing mitochondrial fission as an emerging therapeutic target.

Keywords:  apoptosis; cancer; cardiolipin (CL); dynamin 2 (DNM2); dynamin-related protein 1 (Drp1); mitochondrial dynamics protein of 49 kDa (MiD49); mitochondrial dynamics protein of 51 kDa (MiD51); mitochondrial fission factor (MFF); mitochondrial fission protein 1 (Fis1); mitophagy; mitotic fission; phosphatidic acid (PA); pulmonary arterial hypertension

DOI:  https://doi.org/10.3390/cells12141897
Nature. 2023 Jul 24.

Hotly awaited structures obtained for the human protein UCP1.

Michael J Gaudry, Martin Jastroch.



Keywords:  Cell biology; Structural biology

DOI:  https://doi.org/10.1038/d41586-023-02334-w
Blood. 2023 Jul 27. 142(4): 309-311

ZDHHC21: a mitochondrial vulnerability in AML.

Aaron D Schimmer.

DOI: https://doi.org/10.1182/blood.2023021129