bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–08–27
eight papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Structural mechanism of mitochondrial membrane remodelling by human OPA1.
  2. OPA1 helical structures give perspective to mitochondrial dysfunction.
  3. Nix interacts with WIPI2 to induce mitophagy.
  4. PINK1 and Parkin regulate IP3R-mediated ER calcium release.
  5. Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
  6. The Transcription Factor ChREBP Links Mitochondrial Lipidomes to Mitochondrial Morphology and Progression of Diabetic Kidney Disease.
  7. AMPK promotes lysosomal and mitochondrial biogenesis via folliculin:FNIP1.
  8. APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants.
  1. Nature. 2023 Aug 23.
    Structural mechanism of mitochondrial membrane remodelling by human OPA1.
    Alexander von der Malsburg, Gracie M Sapp, Kelly E Zuccaro, Alexander von Appen, Frank R Moss, Raghav Kalia, Jeremy A Bennett, Luciano A Abriata, Matteo Dal Peraro, Martin van der Laan, Adam Frost, Halil Aydin.
      Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1-3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
    DOI:  https://doi.org/10.1038/s41586-023-06441-6
  2. Nature. 2023 Aug 23.
    OPA1 helical structures give perspective to mitochondrial dysfunction.
    Sarah B Nyenhuis, Xufeng Wu, Marie-Paule Strub, Yang-In Yim, Abigail E Stanton, Valentina Baena, Zulfeqhar A Syed, Bertram Canagarajah, John A Hammer, Jenny E Hinshaw.
      Dominant optic atrophy is one of the leading causes of childhood blindness. Around 60-80% of cases1 are caused by mutations of the gene that encodes optic atrophy protein 1 (OPA1), a protein that has a key role in inner mitochondrial membrane fusion and remodelling of cristae and is crucial for the dynamic organization and regulation of mitochondria2. Mutations in OPA1 result in the dysregulation of the GTPase-mediated fusion process of the mitochondrial inner and outer membranes3. Here we used cryo-electron microscopy methods to solve helical structures of OPA1 assembled on lipid membrane tubes, in the presence and absence of nucleotide. These helical assemblies organize into densely packed protein rungs with minimal inter-rung connectivity, and exhibit nucleotide-dependent dimerization of the GTPase domains-a hallmark of the dynamin superfamily of proteins4. OPA1 also contains several unique secondary structures in the paddle domain that strengthen its membrane association, including membrane-inserting helices. The structural features identified in this study shed light on the effects of pathogenic point mutations on protein folding, inter-protein assembly and membrane interactions. Furthermore, mutations that disrupt the assembly interfaces and membrane binding of OPA1 cause mitochondrial fragmentation in cell-based assays, providing evidence of the biological relevance of these interactions.
    DOI:  https://doi.org/10.1038/s41586-023-06462-1
  3. EMBO J. 2023 Aug 25. e113491
    Nix interacts with WIPI2 to induce mitophagy.
    Eric N Bunker, François Le Guerroué, Chunxin Wang, Marie-Paule Strub, Achim Werner, Nico Tjandra, Richard J Youle.
      Nix is a membrane-anchored outer mitochondrial protein that induces mitophagy. While Nix has an LC3-interacting (LIR) motif that binds to ATG8 proteins, it also contains a minimal essential region (MER) that induces mitophagy through an unknown mechanism. We used chemically induced dimerization (CID) to probe the mechanism of Nix-mediated mitophagy and found that both the LIR and MER are required for robust mitophagy. We find that the Nix MER interacts with the autophagy effector WIPI2 and recruits WIPI2 to mitochondria. The Nix LIR motif is also required for robust mitophagy and converts a homogeneous WIPI2 distribution on the surface of the mitochondria into puncta, even in the absence of ATG8s. Together, this work reveals unanticipated mechanisms in Nix-induced mitophagy and the elusive role of the MER, while also describing an interesting example of autophagy induction that acts downstream of the canonical initiation complexes.
    Keywords:  Autophagy; BNIP3; FIP200; LIR; p62
    DOI:  https://doi.org/10.15252/embj.2023113491
  4. Nat Commun. 2023 Aug 25. 14(1): 5202
    PINK1 and Parkin regulate IP3R-mediated ER calcium release.
    Su Jin Ham, Heesuk Yoo, Daihn Woo, Da Hyun Lee, Kyu-Sang Park, Jongkyeong Chung.
      Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-40929-z
  5. Aging Cell. 2023 Aug 23. e13954
    Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
    Natalia Oleinik, Onder Albayram, Mohamed Faisal Kassir, F Cansu Atilgan, Chase Walton, Eda Karakaya, John Kurtz, Alexander Alekseyenko, Habeeb Alsudani, Megan Sheridan, Zdzislaw M Szulc, Besim Ogretmen.
      The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).
    Keywords:  CerS1; Drp1; aging; ceramide; mitochondrial metabolism; mitophagy; neurodegeneration; sensorimotor defects
    DOI:  https://doi.org/10.1111/acel.13954
  6. J Biol Chem. 2023 Aug 21. pii: S0021-9258(23)02213-5. [Epub ahead of print] 105185
    The Transcription Factor ChREBP Links Mitochondrial Lipidomes to Mitochondrial Morphology and Progression of Diabetic Kidney Disease.
    Li Li, Jianyin Long, Koki Mise, Naravat Poungavrin, Philip L Lorenzi, Iqbal Mahmud, Lin Tan, Pradip K Saha, Yashpal S Kanwar, Benny H Chang, Farhad R Danesh.
      A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. Because of the critical role of ChREBP in lipid metabolism, we interrogated whether and how mitochondrial lipidomes play a role in ChREBP-mediated mitochondrial fission. Our findings suggest a key role for a family of ether phospholipids in ChREBP-induced mitochondrial remodeling. We find that overexpression of glyceronephosphate O-acyltransferase (GNPAT), a critical enzyme in the biosynthesis of plasmalogens, reverses the protective phenotype of ChREBP deficiency on mitochondrial fragmentation. Finally, our data also points to Gnpat as a direct transcriptional target of ChREBP. Taken together, our results uncover a distinct mitochondrial lipid signature as the link between ChREBP-induced mitochondrial dynamics and progression of DKD.
    Keywords:  diabetic nephropathy; kidney metabolism; lipid metabolism; mitochondria; phospholipid
    DOI:  https://doi.org/10.1016/j.jbc.2023.105185
  7. Life Metab. 2023 Oct;2(5): load027
    AMPK promotes lysosomal and mitochondrial biogenesis via folliculin:FNIP1.
    Jordana B Freemantle, D Grahame Hardie.
      The AMP-activated protein kinase (AMPK) is known to maintain the integrity of cellular mitochondrial networks by (i) promoting fission, (ii) inhibiting fusion, (iii) promoting recycling of damaged components via mitophagy, (iv) enhancing lysosomal biogenesis to support mitophagy, and (v) promoting biogenesis of new mitochondrial components. While the AMPK targets underlying the first three of these effects are known, a recent paper suggests that direct phosphorylation of the folliculin-interacting protein 1 (FNIP1) by AMPK may be involved in the remaining two.
    DOI:  https://doi.org/10.1093/lifemeta/load027
  8. Nat Commun. 2023 Aug 19. 14(1): 5058
    APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants.
    Salvatore Daniele Bianco, Luca Parca, Francesco Petrizzelli, Tommaso Biagini, Agnese Giovannetti, Niccolò Liorni, Alessandro Napoli, Massimo Carella, Vincent Procaccio, Marie T Lott, Shiping Zhang, Angelo Luigi Vescovi, Douglas C Wallace, Viviana Caputo, Tommaso Mazza.
      Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics.
    DOI:  https://doi.org/10.1038/s41467-023-40797-7
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