bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–01–07
twelve papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.
  2. The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.
  3. Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
  4. HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
  5. Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
  6. Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif.
  7. MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
  8. The biology of mitochondrial carrier homolog 2.
  9. The mitochondrial protease PARL is required for spermatogenesis.
  10. Mitochondrial-derived vesicles in metabolism, disease, and aging.
  11. Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
  12. Fission-independent compartmentalization of mitochondria during budding yeast cell division.
  1. Mol Cell. 2023 Dec 20. pii: S1097-2765(23)01027-4. [Epub ahead of print]
    Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.
    Xiaojian Shi, Marisa DeCiucis, Kariona A Grabinska, Jean Kanyo, Adam Liu, Tukiet T Lam, Hongying Shen.
      Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR knockout (KO) in mammalian cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.
    Keywords:  AFG3L2; SLC25A39; glutathione; iron; mitochondrial transporter; protein quality control
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.008
  2. EMBO J. 2024 Jan;43(1): 32-60
    The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.
    Jose M Delgado, Logan Wallace Shepard, Sarah W Lamson, Samantha L Liu, Christopher J Shoemaker.
      Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. This screen revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system and the ubiquitin-proteosome system regulated BNIP3 independently. Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. More broadly, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that tightly regulate endogenous tail-anchored protein localization.
    Keywords:  BNIP3; EMC; Mitophagy; Secretory Pathway; TA Protein
    DOI:  https://doi.org/10.1038/s44318-023-00006-z
  3. EMBO J. 2024 Jan 02.
    Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
    Zhan Yin, Ahmed-Noor A Agip, Hannah R Bridges, Judy Hirst.
      Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.
    Keywords:  Complex I; Cryo-EM; Leigh Syndrome; Mitochondria; NADH:Ubiquinone Oxidoreductase
    DOI:  https://doi.org/10.1038/s44318-023-00001-4
  4. Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2306454120
    HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
    Mengying Cui, Koji Yamano, Kenichi Yamamoto, Hitomi Yamamoto-Imoto, Satoshi Minami, Takeshi Yamamoto, Sho Matsui, Tatsuya Kaminishi, Takayuki Shima, Monami Ogura, Megumi Tsuchiya, Kohei Nishino, Brian T Layden, Hisakazu Kato, Hidesato Ogawa, Shinya Oki, Yukinori Okada, Yoshitaka Isaka, Hidetaka Kosako, Noriyuki Matsuda, Tamotsu Yoshimori, Shuhei Nakamura.
      Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation-qPCR, we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB-HKDC1 axis was essential for PINK1 (PTEN-induced kinase 1)/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels, with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and maintaining mitochondria-lysosome contact. Interestingly, HKDC1 regulated mitophagy and lysosomal repair independently of its prospective function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage-induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.
    Keywords:  HKDC1; TFEB; cellular senescence; mitochondria–lysosome contact; mitophagy
    DOI:  https://doi.org/10.1073/pnas.2306454120
  5. Nat Commun. 2024 Jan 02. 15(1): 168
    Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
    Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song, He He.
      Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
    DOI:  https://doi.org/10.1038/s41467-023-44057-6
  6. Nat Commun. 2024 Jan 02. 15(1): 52
    Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif.
    Isabel Pérez-Jover, Kristy Rochon, Di Hu, Mukesh Mahajan, Pooja Madan Mohan, Isaac Santos-Pérez, Julene Ormaetxea Gisasola, Juan Manuel Martinez Galvez, Jon Agirre, Xin Qi, Jason A Mears, Anna V Shnyrova, Rajesh Ramachandran.
      The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo. Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, surprisingly leading to the fission of model membranes in vitro. In vivo, the involvement of the native CT-SLiM is critical for productive mitochondrial and peroxisomal fission, as both deletion and non-native extension of the CT-SLiM severely impair their progression. Thus, contrary to prevailing models, Drp1-catalyzed membrane fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.
    DOI:  https://doi.org/10.1038/s41467-023-44413-6
  7. EMBO Rep. 2023 Dec 14.
    MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
    Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, Atan Gross.
      Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.
    Keywords:  LPA; MFN2; MTCH2; Mitochondria-ER Communication; Mitochondrial Fusion
    DOI:  https://doi.org/10.1038/s44319-023-00009-1
  8. Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00117-4. [Epub ahead of print]75 101837
    The biology of mitochondrial carrier homolog 2.
    Xiaohe Zheng, Binxiang Chu.
      The mitochondrial carrier system is in charge of small molecule transport between the mitochondria and the cytoplasm as well as being an integral portion of the core mitochondrial function. One member of the mitochondrial carrier family of proteins, mitochondrial carrier homolog 2 (MTCH2), is characterized as a critical mitochondrial outer membrane protein insertase participating in mitochondrial homeostasis. Accumulating evidence demonstrate that MTCH2 is integrally linked to cell death and mitochondrial metabolism, and its genetic alterations cause a variety of disease phenotypes, ranging from obesity, Alzheimer's disease, and tumor. To provide a comprehensive insight into the current understanding of MTCH2, we present a detailed description of the physiopathological functions of MTCH2, ranging from apoptosis, mitochondrial dynamics, and metabolic homeostasis regulation. Moreover, we summarized the impact of MTCH2 in human diseases, and highlighted tumors, to assess the role of MTCH2 mutations or variable expression on pathogenesis and target therapeutic options.
    Keywords:  Apoptosis; Lipid metabolism; MTCH2; Mitochondria; Tumor
    DOI:  https://doi.org/10.1016/j.mito.2023.101837
  9. Commun Biol. 2024 Jan 05. 7(1): 44
    The mitochondrial protease PARL is required for spermatogenesis.
    Sarah Schumacher, Laura Klose, Jessica Lambertz, Dieter Lütjohann, Ronald Biemann, Stefanie Kuerten, Lars Fester.
      Mitochondrial function plays an important role in the maintenance of male fertility. However, the mechanisms underlying mitochondrial defect-related infertility remain mostly unclear. Here we show that a deficiency of PARL (Parl-/-), a mitochondrial protease, causes complete arrest of spermatogenesis during meiosis I. PARL deficiency led to severe downregulation of proteins of respiratory chain complex IV in testes that did not occur in other tested organs, causing a deficit in complex IV activity and ATP production. Furthermore, Parl-/- testes showed an almost complete loss of HSD17B3, a protein of the sER responsible for the last step in testosterone synthesis. While testosterone production appeared to be restored by overexpression of HSD17B12, loss of the canonical testosterone synthesis led to an upregulation of luteinizing hormone (LH) and of LH-regulated responses. These results suggest an important impact of the downstream regulation of mitochondrial defects that manifest in a cell-type-specific manner and extend beyond mitochondria.
    DOI:  https://doi.org/10.1038/s42003-023-05703-3
  10. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00446-1. [Epub ahead of print]36(1): 21-35
    Mitochondrial-derived vesicles in metabolism, disease, and aging.
    Tim König, Heidi M McBride.
      Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.014
  11. Annu Rev Biophys. 2024 Jan 02.
    Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling and immune responses. They are highly dynamic at different structural and functional levels. Mitochondria have been shown to constantly undergo fusion and fission processes and dynamically interact with other organelles such as the endoplasmic reticulum, peroxisomes, and lipid droplets. The field of mitochondrial dynamics has evolved hand in hand with technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling of the cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer of mitochondrial dynamics. In this review, we discuss mitochondrial dynamics at the following levels: (a) within an individual mitochondrion, (b) among mitochondria, and (c) between mitochondria and other organelles. Although the three tiers of mitochondrial dynamics have in the past been classified in a hierarchical manner, they are functionally connected and must act in a coordinated manner to maintain cellular functions and thus prevent various human diseases. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biophys-030822-020736
  12. J Cell Biol. 2024 Mar 04. pii: e202211048. [Epub ahead of print]223(3):
    Fission-independent compartmentalization of mitochondria during budding yeast cell division.
    Saori R Yoshii, Yves Barral.
      Lateral diffusion barriers compartmentalize membranes to generate polarity or asymmetrically partition membrane-associated macromolecules. Budding yeasts assemble such barriers in the endoplasmic reticulum (ER) and the outer nuclear envelope at the bud neck to retain aging factors in the mother cell and generate naïve and rejuvenated daughter cells. However, little is known about whether other organelles are similarly compartmentalized. Here, we show that the membranes of mitochondria are laterally compartmentalized at the bud neck and near the cell poles. The barriers in the inner mitochondrial membrane are constitutive, whereas those in the outer membrane form in response to stresses. The strength of mitochondrial diffusion barriers is regulated positively by spatial cues from the septin axis and negatively by retrograde (RTG) signaling. These data indicate that mitochondria are compartmentalized in a fission-independent manner. We propose that these diffusion barriers promote mitochondrial polarity and contribute to mitochondrial quality control.
    DOI:  https://doi.org/10.1083/jcb.202211048
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