bims-mitdyn 2022-04-03 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2022–04–03
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine

Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy.
Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.
Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.
NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment.
Mitochondrial Protein Translocation Machinery: From TOM Structural Biogenesis to Functional Regulation.
Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.
Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
Starting the engine of the powerhouse: mitochondrial transcription and beyond.
Analysis of Mitochondrial Dysfunction by Microplate Reader in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Disorders.
Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation.

Mol Cell. 2022 Mar 29. pii: S1097-2765(22)00221-0. [Epub ahead of print]

Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy.

Ellen A Goodall, Felix Kraus, J Wade Harper.

  Selective autophagy specifically eliminates damaged or superfluous organelles, maintaining cellular health. In this process, a double membrane structure termed an autophagosome captures target organelles or proteins and delivers this cargo to the lysosome for degradation. The attachment of the small protein ubiquitin to cargo has emerged as a common mechanism for initiating organelle or protein capture by the autophagy machinery. In this process, a suite of ubiquitin-binding cargo receptors function to initiate autophagosome assembly in situ on the target cargo, thereby providing selectivity in cargo capture. Here, we review recent efforts to understand the biochemical mechanisms and principles by which cargo are marked with ubiquitin and how ubiquitin-binding cargo receptors use conserved structural modules to recruit the autophagosome initiation machinery, with a particular focus on mitochondria and intracellular bacteria as cargo. These emerging mechanisms provide answers to long-standing questions in the field concerning how selectivity in cargo degradation is achieved.

Keywords:  cargo receptor; mitophagy; selective autophagy; ubiquitin; xenophagy

DOI:  https://doi.org/10.1016/j.molcel.2022.03.012
Proc Natl Acad Sci U S A. 2022 Apr 05. 119(14): e2121946119

Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.

Latika Nagpal, Michael D Kornberg, Solomon H Snyder.

  SignificanceInositol pyrophosphates are versatile messenger molecules containing the energetic pyrophosphate bond. One of the principal enzymes generating the inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate) is inositol hexakisphosphate kinase 2 (IP6K2). Previous work has shown that IP6K2 is neuroprotective and maintains mitochondrial respiration. We now report that loss of IP6K2 leads to increased mitochondrial fission and mitophagy. Regulation of mitochondrial dynamics by IP6K2 depends on the protein PINK1 and, interestingly, is independent of IP6K2 enzymatic activity. These findings provide mechanistic insight into the regulation of mitochondrial function by IP6K2, which has implications for neuroprotection and mitochondrial physiology more generally.

Keywords:  PINK1; inositol phosphate; mitochondrial biogenesis; mitophagy; neuroprotection

DOI:  https://doi.org/10.1073/pnas.2121946119
Autophagy. 2022 Mar 29. 1-3

Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.

Juliet Goldsmith, Erika L F Holzbaur.

  Neurons depend on macroautophagy/autophagy to maintain cellular homeostasis, and loss of autophagy leads to neurodegeneration. To better understand the role of basal autophagy in neurons, we enriched autophagic vesicles from healthy adult mouse brain and performed mass spectrometry to identify cargos cleared by autophagy. We found that synaptic and mitochondrial proteins comprise nearly half of the unique AV cargos identified in brain. Similarly, synaptic and mitochondrial proteins are major cargos for basal autophagy in neurons. Strikingly, we noted a specific enrichment of mitochondrial nucleoids within neuronal autophagosomes, which occurs through a mechanism distinct from damage-associated mitophagy. Here, we discuss the implications of these findings for our understanding of homeostatic mechanisms in neurons and how the age-dependent decline of autophagy in neurons may contribute to the onset or progression of neurodegenerative disease.

Keywords:  DNM1L; SYN1; TFAM; macroautophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis

DOI:  https://doi.org/10.1080/15548627.2022.2056865
Oncogene. 2022 Mar 30.

NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment.

Irene Bertolini, Michela Perego, Jagadish C Ghosh, Andrew V Kossenkov, Dario C Altieri.

Small extracellular vesicles (sEV) contribute to the crosstalk between tumor cells and stroma, but the underlying signals are elusive. Here, we show that sEV generated by breast cancer cells in hypoxic (sEVHYP), but not normoxic (sEVNORM) conditions activate NFκB in recipient normal mammary epithelial cells. This increases the production and release of inflammatory cytokines, promotes mitochondrial dynamics leading to heightened cell motility and disrupts 3D mammary acini architecture with aberrant cell proliferation, reduced apoptosis and EMT. Mechanistically, Integrin-Linked Kinase packaged in sEVHYP via HIF1α is sufficient to activate NFκB in the normal mammary epithelium, in vivo. Therefore, sEVHYP activation of NFκB drives multiple oncogenic steps of inflammation, mitochondrial dynamics, and mammary gland morphogenesis in a breast cancer microenvironment.

DOI: https://doi.org/10.1038/s41388-022-02280-3
J Biol Chem. 2022 Mar 25. pii: S0021-9258(22)00310-6. [Epub ahead of print] 101870

Mitochondrial Protein Translocation Machinery: From TOM Structural Biogenesis to Functional Regulation.

Ulfat Mohd Hanif Sayyed, Radhakrishnan Mahalakshmi.

  The human mitochondrial outer membrane is biophysically unique as it is the only membrane possessing transmembrane β-barrel proteins (mitochondrial outer membrane proteins, mOMPs) in the cell. The most vital of the three mOMPs is the core protein of the translocase of the outer mitochondrial membrane (TOM) complex. Identified first as MOM38 in Neurospora in 1990, the structure of Tom40, the core 19-stranded β-barrel translocation channel, was solved in 2017, after nearly three decades. Remarkably, the past four years have witnessed an exponential increase in structural and functional studies of yeast and human TOM complexes. In addition to being conserved across all eukaryotes, the TOM complex is the sole ATP-independent import machinery for nearly all of the ∼1000-1500 known mitochondrial proteins. Recent cryo-EM structures have provided detailed insight into both possible assembly mechanisms of the TOM core complex and organizational dynamics of the import machinery, and now reveal novel regulatory interplay with other mOMPs. Functional characterization of the TOM complex using biochemical and structural approaches has also revealed mechanisms for substrate recognition and at least five defined import pathways for precursor proteins. In this review, we discuss the discovery, recently solved structures, molecular function, and regulation of the TOM complex and its constituents, along with the implications these advances have for human diseases.

Keywords:  TOM complex; Tom40; dysregulation; mitochondrial outer membrane; protein import pathways; transmembrane β-barrels

DOI:  https://doi.org/10.1016/j.jbc.2022.101870
Br J Pharmacol. 2022 Mar 30.

Targeting Mitochondrial Proteases for Therapy of Acute Myeloid Leukemia.

Xinrong Xiang, Rui Bao, Yu Wu, Youfu Luo.

  Targeting cancer metabolism has emerged as an attractive approach to improve therapeutic regimens in acute myeloid leukemia (AML). Mitochondrial proteases are closely related to cancer metabolism, but their biological functions have not been well characterized in AML. According to different catogory, we comprehensively reviewed the role of mitochondrial proteases in AML. This review highlights some 'powerful' mitochondrial protease targets, including their biological function, chemical modulators, and applicative prospect in AML.

Keywords:  acute myeloid leukemia; mitochondrial metabolism; mitochondrial proteases; oxidative phosphorylation

DOI:  https://doi.org/10.1111/bph.15844
Mol Metab. 2022 Mar 25. pii: S2212-8778(22)00050-3. [Epub ahead of print] 101481

Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.

Aakriti Jain, Roberto Zoncu.

  Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable the concentration of metabolic precursors within optimized chemical environments, greatly accelerating the efficiency of both anabolic and catabolic reactions, enabling division of labor and optimal utilization of resources. However, metabolic compartmentalization also poses a challenge to cells because it creates spatial discontinuities that must be bridged for reaction cascades to be connected and completed. To do so, cells employ different methods to coordinate metabolic fluxes occurring in different organelles, such as membrane-localized transporters to facilitate regulated metabolite exchange between mitochondria and lysosomes, non-vesicular transport pathways via physical contact sites connecting the ER with both mitochondria and lysosomes, as well as localized regulatory signaling processes that coordinately regulate the activity of all these organelles. Effective communication among these systems is essential to cellular health and function, whereas disruption of inter-organelle communication is an emerging driver in a multitude of diseases, from cancer to neurodegeneration.

Keywords:  Contact sites; Lysosome; Metabolism; Mitochondria; Transporters; mTORC1

DOI:  https://doi.org/10.1016/j.molmet.2022.101481
Biol Chem. 2022 Mar 31.

Starting the engine of the powerhouse: mitochondrial transcription and beyond.

Maria Miranda, Nina A Bonekamp, Inge Kühl.

  Mitochondria are central hubs for cellular metabolism, coordinating a variety of metabolic reactions crucial for human health. Mitochondria provide most of the cellular energy via their oxidative phosphorylation (OXPHOS) system, which requires the coordinated expression of genes encoded by both the nuclear (nDNA) and mitochondrial genomes (mtDNA). Transcription of mtDNA is not only essential for the biogenesis of the OXPHOS system, but also generates RNA primers necessary to initiate mtDNA replication. Like the prokaryotic system, mitochondria have no membrane-based compartmentalization to separate the different steps of mtDNA maintenance and expression and depend entirely on nDNA-encoded factors imported into the organelle. Our understanding of mitochondrial transcription in mammalian cells has largely progressed, but the mechanisms regulating mtDNA gene expression are still poorly understood despite their profound importance for human disease. Here, we review mechanisms of mitochondrial gene expression with a focus on the recent findings in the field of mammalian mtDNA transcription and disease phenotypes caused by defects in proteins involved in this process.

Keywords:   inhibitor of mitochondrial transcription; PPR proteins; mitochondria; mitochondrial disease; mitochondrial gene expression; mitochondrial transcription

DOI:  https://doi.org/10.1515/hsz-2021-0416
Methods Mol Biol. 2022 Mar 29.

Analysis of Mitochondrial Dysfunction by Microplate Reader in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Disorders.

Tatiana R Rosenstock, Congxin Sun, Georgina Wynne Hughes, Katherine Winter, Sovan Sarkar.

  Mitochondria are responsible for many vital pathways governing cellular homeostasis, including cellular energy management, heme biosynthesis, lipid metabolism, cellular proliferation and differentiation, cell cycle regulation, and cellular viability. Electron transport and ADP phosphorylation coupled with proton pumping through the mitochondrial complexes contribute to the preservation of mitochondrial membrane potential (ΔΨm). Importantly, mitochondrial polarization is essential for reactive oxygen species (ROS) production and cytosolic calcium (Ca2+) handling. Thus, changes in mitochondrial oxidative phosphorylation (OXPHOS), ΔΨm, and ATP/ADP may occur in parallel or stimulate each other. Brain cells like neurons are heavily reliant on mitochondrial OXPHOS for its high-energy demands, and hence improper mitochondrial function is detrimental for neuronal survival. Indeed, several neurodegenerative disorders are associated with mitochondrial dysfunction. Modeling this disease-relevant phenotype in neuronal cells differentiated from patient-derived human induced pluripotent stem cells (hiPSCs) provide an appropriate cellular platform for studying the disease pathology and drug discovery. In this review, we describe high-throughput analysis of crucial parameters related to mitochondrial function in hiPSC-derived neurons. These methodologies include measurement of ΔΨm, intracellular Ca2+, oxidative stress, and ATP/ADP levels using fluorescence probes via a microplate reader. Benefits of such an approach include analysis of mitochondrial parameters on a large population of cells, simultaneous analysis of different cell lines and experimental conditions, and for drug screening to identify compounds restoring mitochondrial function.

Keywords:  Fluorescent dyes; Human induced pluripotent stem cells; Microplate reader; Mitochondria; Mitochondrial calcium; Mitochondrial dysfunction; Mitochondrial membrane potential; Mitochondrial superoxide; Neurodegenerative disease; Neuronal differentiation; Reactive oxygen species; hiPSC-derived neurons

DOI:  https://doi.org/10.1007/7651_2021_451
Mitochondrion. 2022 Mar 25. pii: S1567-7249(22)00025-3. [Epub ahead of print]64 73-81

Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation.

Claus Desler, Jon Ambæk Durhuus, Thomas Lau-Lindestrand Hansen, Sharath Anugula, Nadia Thaulov Zelander, Sisse Bøggild, Lene Juel Rasmussen.

  The correlation between mitochondrial function and oncogenesis is complex and is not fully understood. Here we determine the importance of mitochondrial-linked pyrimidine synthesis for the aggressiveness of cancer cells. The enzyme dihydroorotate dehydrogenase (DHODH) links oxidative phosphorylation to de novo synthesis of pyrimidines. We demonstrate that an inhibition of DHODH results in a respiration-independent significant increase of anchorage-independent growth but does not affect DNA repair ability. Instead, we show an autophagy-independent increase of lysosomes. The results of this study suggest that inhibition of mitochondrial-linked pyrimidine synthesis in cancer cells results in a more aggressive tumor phenotype.

Keywords:  DNA repair; Lysosome increase; Mitochondria; Mitochondrial-linked pyrimidine synthesis; Tumorigenesis

DOI:  https://doi.org/10.1016/j.mito.2022.03.005