bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022–02–13
twelve papers selected by
Avinash N. Mukkala, University of Toronto
  1. The fate of damaged mitochondrial DNA in the cell.
  2. Acute exercise rapidly activates hepatic mitophagic flux.
  3. Mitophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention.
  4. In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
  5. Visualization of Dynamic Mitochondrial Calcium Fluxes in Isolated Cardiomyocytes.
  6. PINK spots: diseased mitochondria prepare for mitophagy.
  7. Spatial and temporal control of mitochondrial H2 O2 release in intact human cells.
  8. Tourniquet-induced lower limb ischemia/reperfusion reduces mitochondrial function by decreasing mitochondrial biogenesis in acute kidney injury in mice.
  9. Delivery of mitochondria via extracellular vesicles - A new horizon in drug delivery.
  10. Proteomic analysis of the mitochondrial glucocorticoid receptor interacting proteins reveals pyruvate dehydrogenase and mitochondrial 60 kDa heat shock protein as potent binding partners.
  11. Protocol to characterize mitochondrial supercomplexes from mouse tissues by combining BN-PAGE and MS-based proteomics.
  12. Therapeutic regulation of autophagy in hepatic metabolism.
  1. Biochim Biophys Acta Mol Cell Res. 2022 Feb 04. pii: S0167-4889(22)00024-6. [Epub ahead of print] 119233
    The fate of damaged mitochondrial DNA in the cell.
    Siyang Liao, Li Chen, Zhiyin Song, He He.
      Mitochondrion is a double membrane organelle that is responsible for cellular respiration and production of most of the ATP in eukaryotic cells. Mitochondrial DNA (mtDNA) is the genetic material carried by mitochondria, which encodes some essential subunits of respiratory complexes independent of nuclear DNA. Normally, mtDNA binds to certain proteins to form a nucleoid that is stable in mitochondria. Nevertheless, a variety of physiological or pathological stresses can cause mtDNA damage, and the accumulation of damaged mtDNA in mitochondria leads to mitochondrial dysfunction, which triggers the occurrence of mitochondrial diseases in vivo. In response to mtDNA damage, cell initiates multiple pathways including mtDNA repair, degradation, clearance and release, to recover mtDNA, and maintain mitochondrial quality and cell homeostasis. In this review, we provide our current understanding of the fate of damaged mtDNA, focus on the pathways and mechanisms of removing damaged mtDNA in the cell.
    Keywords:  Mitochondria DNA (mtDNA); Mitocytosis; Mitophagy; mtDNA release
    DOI:  https://doi.org/10.1016/j.bbamcr.2022.119233
  2. J Appl Physiol (1985). 2022 Feb 10.
    Acute exercise rapidly activates hepatic mitophagic flux.
    Colin S McCoin, Edziu Franczak, Fengyan Deng, Dong Pei, Wen-Xing Ding, John P Thyfault.
      Exercise is critical for improving metabolic health and putatively maintains or enhances mitochondrial quality control in metabolic tissues. While previous work has shown exercise elicits hepatic mitochondrial biogenesis, it is unknown if acute exercise activates hepatic mitophagy, the selective degradation of damaged or low-functioning mitochondria. We tested if an acute bout of treadmill running increased hepatic mitophagic flux both immediately after and 2 hours post-exercise in 15-24-week-old C57BL/6J female mice. Acute exercise did not significantly increase markers of autophagic flux, however, mitophagic flux was activated 2 hours post-treadmill running as measured by accumulation of both LC3-II and p62 in isolated mitochondria in the presence of leupeptin, an inhibitor of autophagosome degradation. Further, mitochondrial associated ubiquitin, which recruits the autophagy receptor protein p62, was also significantly increased at 2 hours. Further examination via western blot and proteomics analysis revealed acute exercise elicits a time-dependent, dynamic activation of mitophagy pathways. Moreover, the results suggest that exercise induced hepatic mitophagy is likely mediated by both poly-ubiquitination and receptor mediated signaling pathways. Overall, we provide evidence that acute exercise activates hepatic mitophagic flux while also revealing specific receptor-mediated proteins by which exercise maintains mitochondrial quality control in the liver.
    Keywords:  Exercise; Liver; Mitochondria; Mitophagic Flux; Mitophagy
    DOI:  https://doi.org/10.1152/japplphysiol.00704.2021
  3. Oxid Med Cell Longev. 2022 ;2022 4906434
    Mitophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention.
    Mingrui Zhu, Xinqi Huang, Haiyan Shan, Mingyang Zhang.
      Traumatic brain injury (TBI) contributes to death, and disability worldwide more than any other traumatic insult and damage to cellular components including mitochondria leads to the impairment of cellular functions and brain function. In neurons, mitophagy, autophagy-mediated degradation of damaged mitochondria, is a key process in cellular quality control including mitochondrial homeostasis and energy supply and plays a fundamental role in neuronal survival and health. Conversely, defective mitophagy leads to the accumulation of damaged mitochondria and cellular dysfunction, contributing to inflammation, oxidative stress, and neuronal cell death. Therefore, an extensive characterization of mitophagy-related protective mechanisms, taking into account the complex mechanisms by which each molecular player is connected to the others, may provide a rationale for the development of new therapeutic strategies in TBI patients. Here, we discuss the contribution of defective mitophagy in TBI, and the underlying molecular mechanisms of mitophagy in inflammation, oxidative stress, and neuronal cell death highlight novel therapeutics based on newly discovered mitophagy-inducing strategies.
    DOI:  https://doi.org/10.1155/2022/4906434
  4. Nat Commun. 2022 Feb 08. 13(1): 750
    In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
    Pedro Silva-Pinheiro, Pavel A Nash, Lindsey Van Haute, Christian D Mutti, Keira Turner, Michal Minczuk.
      Mitochondria host key metabolic processes vital for cellular energy provision and are central to cell fate decisions. They are subjected to unique genetic control by both nuclear DNA and their own multi-copy genome - mitochondrial DNA (mtDNA). Mutations in mtDNA often lead to clinically heterogeneous, maternally inherited diseases that display different organ-specific presentation at any stage of life. For a long time, genetic manipulation of mammalian mtDNA has posed a major challenge, impeding our ability to understand the basic mitochondrial biology and mechanisms underpinning mitochondrial disease. However, an important new tool for mtDNA mutagenesis has emerged recently, namely double-stranded DNA deaminase (DddA)-derived cytosine base editor (DdCBE). Here, we test this emerging tool for in vivo use, by delivering DdCBEs into mouse heart using adeno-associated virus (AAV) vectors and show that it can install desired mtDNA edits in adult and neonatal mice. This work provides proof-of-concept for use of DdCBEs to mutagenize mtDNA in vivo in post-mitotic tissues and provides crucial insights into potential translation to human somatic gene correction therapies to treat primary mitochondrial disease phenotypes.
    DOI:  https://doi.org/10.1038/s41467-022-28358-w
  5. Front Physiol. 2021 ;12 808798
    Visualization of Dynamic Mitochondrial Calcium Fluxes in Isolated Cardiomyocytes.
    Anna Maria Krstic, Amelia Sally Power, Marie-Louise Ward.
       Background: Cardiomyocyte contraction requires a constant supply of ATP, which varies depending on work rate. Maintaining ATP supply is particularly important during excitation-contraction coupling, where cytosolic Ca2+ fluxes drive repeated cycles of contraction and relaxation. Ca2+ is one of the key regulators of ATP production, and its uptake into the mitochondrial matrix occurs via the mitochondrial calcium uniporter. Fluorescent indicators are commonly used for detecting cytosolic Ca2+ changes. However, visualizing mitochondrial Ca2+ fluxes using similar methods is more difficult, as the fluorophore must be permeable to both the sarcolemma and the inner mitochondrial membrane. Our aim was therefore to optimize a method using the fluorescent Ca2+ indicator Rhod-2 to visualize beat-to-beat mitochondrial calcium fluxes in rat cardiomyocytes.
    Methods: Healthy, adult male Wistar rat hearts were isolated and enzymatically digested to yield rod-shaped, quiescent ventricular cardiomyocytes. The fluorescent Ca2+ indicator Rhod-2 was reduced to di-hydroRhod-2 and confocal microscopy was used to validate mitochondrial compartmentalization. Cardiomyocytes were subjected to various pharmacological interventions, including caffeine and β-adrenergic stimulation. Upon confirmation of mitochondrial Rhod-2 localization, loaded myocytes were then super-fused with 1.5 mM Ca2+ Tyrodes containing 1 μM isoproterenol and 150 μM spermine. Myocytes were externally stimulated at 0.1, 0.5 and 1 Hz and whole cell recordings of both cytosolic ([Ca2+]cyto) and mitochondrial calcium ([Ca2+] mito ) transients were made.
    Results: Myocytes loaded with di-hydroRhod-2 revealed a distinct mitochondrial pattern when visualized by confocal microscopy. Application of 20 mM caffeine revealed no change in fluorescence, confirming no sarcoplasmic reticulum compartmentalization. Myocytes loaded with di-hydroRhod-2 also showed a large increase in fluorescence within the mitochondria in response to β-adrenergic stimulation (P < 0.05). Beat-to-beat mitochondrial Ca2+ transients were smaller in amplitude and had a slower time to peak and maximum rate of rise relative to cytosolic calcium transients at all stimulation frequencies (P < 0.001).
    Conclusion: Myocytes loaded with di-hydroRhod-2 revealed mitochondrial specific compartmentalization. Mitochondrial Ca2+ transients recorded from di-hydroRhod-2 loaded myocytes were distinct in comparison to the large and rapid Rhod-2 cytosolic transients, indicating different kinetics between [Ca2+]cyto and [Ca2+]mito transients. Overall, our results showed that di-hydroRhod-2 loading is a quick and suitable method for measuring beat-to-beat [Ca2+]mito transients in intact myocytes.
    Keywords:  calcium; cardiomyocytes; di-hydroRhod-2AM; excitation-contraction coupling; fluxes; mitochondria
    DOI:  https://doi.org/10.3389/fphys.2021.808798
  6. Nat Struct Mol Biol. 2022 Feb 10.
    PINK spots: diseased mitochondria prepare for mitophagy.
    Sara Osman.
      
    DOI:  https://doi.org/10.1038/s41594-022-00733-7
  7. EMBO J. 2022 Feb 11. e109169
    Spatial and temporal control of mitochondrial H2 O2 release in intact human cells.
    Michaela Nicole Hoehne, Lianne J H C Jacobs, Kim Jasmin Lapacz, Gaetano Calabrese, Lena Maria Murschall, Teresa Marker, Harshita Kaul, Aleksandra Trifunovic, Bruce Morgan, Mark Fricker, Vsevolod V Belousov, Jan Riemer.
      Hydrogen peroxide (H2 O2 ) has key signaling roles at physiological levels, while causing molecular damage at elevated concentrations. H2 O2 production by mitochondria is implicated in regulating processes inside and outside these organelles. However, it remains unclear whether and how mitochondria in intact cells release H2 O2 . Here, we employed a genetically encoded high-affinity H2 O2 sensor, HyPer7, in mammalian tissue culture cells to investigate different modes of mitochondrial H2 O2 release. We found substantial heterogeneity of HyPer7 dynamics between individual cells. We further observed mitochondria-released H2 O2 directly at the surface of the organelle and in the bulk cytosol, but not in the nucleus or at the plasma membrane, pointing to steep gradients emanating from mitochondria. Gradient formation is controlled by cytosolic peroxiredoxins, which act redundantly and with a substantial reserve capacity. Dynamic adaptation of cytosolic thioredoxin reductase levels during metabolic changes results in improved H2 O2 handling and explains previously observed differences between cell types. Our data suggest that H2 O2 -mediated signaling is initiated only in close proximity to mitochondria and under specific metabolic conditions.
    Keywords:  HyPer7; hydrogen peroxide release; mitochondria; peroxiredoxin
    DOI:  https://doi.org/10.15252/embj.2021109169
  8. Physiol Rep. 2022 Feb;10(3): e15181
    Tourniquet-induced lower limb ischemia/reperfusion reduces mitochondrial function by decreasing mitochondrial biogenesis in acute kidney injury in mice.
    Balamurugan Packialakshmi, Ian J Stewart, David M Burmeister, Yuanyi Feng, Dennis P McDaniel, Kevin K Chung, Xiaoming Zhou.
      The mechanisms by which lower limb ischemia/reperfusion induces acute kidney injury (AKI) remain largely uncharacterized. We hypothesized that tourniquet-induced lower limb ischemia/reperfusion (TILLIR) would inhibit mitochondrial function in the renal cortex. We used a murine model to show that TILLIR of the high thigh regions inflicted time-dependent AKI as determined by renal function and histology. This effect was associated with decreased activities of mitochondrial complexes I, II, V and citrate synthase in the kidney cortex. Moreover, TILLIR reduced mRNA levels of a master regulator of mitochondrial biogenesis PGC-1α, and its downstream genes NDUFS1 and ATP5o in the renal cortex. TILLIR also increased serum corticosterone concentrations. TILLIR did not significantly affect protein levels of the critical regulators of mitophagy PINK1 and PARK2, mitochondrial transport proteins Tom20 and Tom70, or heat-shock protein 27. TILLIR had no significant effect on mitochondrial oxidative stress as determined by mitochondrial ability to generate reactive oxygen species, protein carbonylation, or protein levels of MnSOD and peroxiredoxin1. However, TILLIR inhibited classic autophagic flux by increasing p62 protein abundance and preventing the conversion of LC3-I to LC3-II. TILLIR increased phosphorylation of cytosolic and mitochondrial ERK1/2 and mitochondrial AKT1, as well as mitochondrial SGK1 activity. In conclusion, lower limb ischemia/reperfusion induces distal AKI by inhibiting mitochondrial function through reducing mitochondrial biogenesis. This AKI occurs without significantly affecting PINK1-PARK2-mediated mitophagy or mitochondrial oxidative stress in the kidney cortex.
    Keywords:  autophagy; ischemia; mitochondrial complex; mitochondrial oxidative stress; mitophagy
    DOI:  https://doi.org/10.14814/phy2.15181
  9. J Control Release. 2022 Feb 04. pii: S0168-3659(22)00067-0. [Epub ahead of print]
    Delivery of mitochondria via extracellular vesicles - A new horizon in drug delivery.
    Devika S Manickam.
      The field of drug delivery has made tremendous advances in increasing the therapeutic potential of a variety of drug candidates spanning from small molecules to large molecular biologics such as nucleic acids, proteins, etc. Extracellular vesicles (EVs) are mediators of intercellular communication and carry a rich cocktail of innate cargo including lipids, proteins and nucleic acids. EVs are being developed as a promising class of natural, cell-derived carriers for drug delivery. EVs of particle diameters <200 nm are referred to as small EVs (sEVs) and medium-to-larger particles of diameters >200 nm are referred to as m/lEVs. The m/lEVs naturally incorporate mitochondria during their biogenesis. In this Oration, I will discuss the potential of m/lEVs as carriers for the delivery of healthy and functional mitochondria. Mitochondrial damage and dysfunction play a causal role in multiple pathologies such as neurodegenerative diseases, cardiovascular and metabolic diseases-suggesting that m/lEV-mediated mitochondria delivery can be of broad biomedical significance. A major advantage of harnessing m/lEVs is that the delivered mitochondria are capable of using endogenous mechanisms for repairing the cellular damage. I will highlight the delivery potential of m/lEVs based on the studies we have conducted so far and discuss unaddressed issues towards their development as a novel class of mitochondria carriers.
    Keywords:  Blood-brain barrier; Medium-to-large extracellular vesicles (m/lEVs); Mitochondria delivery; Neurodegenerative diseases; Stroke
    DOI:  https://doi.org/10.1016/j.jconrel.2022.01.045
  10. J Proteomics. 2022 Feb 03. pii: S1874-3919(22)00032-X. [Epub ahead of print] 104509
    Proteomic analysis of the mitochondrial glucocorticoid receptor interacting proteins reveals pyruvate dehydrogenase and mitochondrial 60 kDa heat shock protein as potent binding partners.
    Aikaterini G Karra, Aikaterini Sioutopoulou, Vyron Gorgogietas, Martina Samiotaki, George Panayotou, Anna-Maria G Psarra.
      Glucocorticoids are steroid hormones that regulate plethora biological actions such as growth and metabolism, immune response, and apoptosis. Glucocorticoids actions are mediated via glucocorticoid receptors which act mainly as transcription factors, but it is also found to be localized in mitochondria. Mitochondrial localization of the receptor indicates novel functions of the receptor. Characterization of the mitochondrial glucocorticoid receptor (mtGR) interacting proteins will shed light on these actions and the biochemical mechanisms that underlie mitochondrial glucocorticoid receptor import and functions. In this study, applying immunoprecipitation, mass spectrometry and Western blot analysis of the GR interacting proteins in total or mitochondrial extracts of HepG2 cells and of HepG2 cells overexpressing a mitochondrial targeted GR we found pyruvate dehydrogenase (PDH), chaperones such as and heat shock protein (HSP) -60, -70, -75 and -90, and 78 kDa glucose-regulated protein, mitochondrial transcription factors and enzymes involved in the regulation of the mitochondrial protein biosynthesis, lipid metabolism, ATP production and apoptosis as glucocorticoid receptor interacting proteins. Our results uncover potential novel mitochondrial partners of the receptor, suggesting possible new regulatory roles of mtGR in the control of mitochondrial-associated functions of the cell. SIGNIFICANCE: In this study the mitochondrial GR interacting proteins were characterized highlighting novel regulatory roles of the receptor in mitochondria. Detection of the mtGR/PDH and mtGR/HSP60 interaction in almost all the analyses performed uncovered PDH and HSP60 proteins as potent mtGR binding partners. The interesting finding of the PDH/mtGR interaction possibly indicates involvement of mtGR in the regulation of the balance between glycolytic and oxidative phosphorylation energy production. Characterization of the mitochondrial heat shock 60, -70, 75 and 78 proteins as mtGR binding partners contribute to the characterization of the biochemical mechanisms of the mitochondrial import of the receptor. Moreover, identification of mitochondrial heat shock proteins, metabolic enzymes, transcription factors, OXPHOS, and regulatory molecules in mitochondrial protein biosynthesis as mtGR binding partners indicates possible new regulatory roles of mtGR in the glucocorticoids-induced regulation and orchestration of nuclear and mitochondrial functions, the exact biochemical mechanism of which remain to be established. The study discloses potential new regulatory roles of the receptor in mitochondria, pointing out its importance as a promising target molecule for the control of the mitochondria-associated pathophysiology of the cell.
    Keywords:  Apoptosis; Energy production; Glucocorticoid receptor; Heat shock proteins; Mitochondria; Pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.jprot.2022.104509
  11. STAR Protoc. 2022 Mar 18. 3(1): 101135
    Protocol to characterize mitochondrial supercomplexes from mouse tissues by combining BN-PAGE and MS-based proteomics.
    Roger Moreno-Justicia, Alba Gonzalez-Franquesa, Ben Stocks, Atul S Deshmukh.
      The assembly of mitochondrial respiratory complexes into supercomplexes has significant implications for mitochondrial function. This protocol details mitochondrial isolation from mouse tissues and the use of blue native gel electrophoresis (BN-PAGE) to separate pre-identified mitochondrial supercomplexes into different gel bands. We then describe the excision of the individual bands, followed by in-gel protein digestion and peptide desalting for mass spectrometry (MS)-based proteomics. This protocol provides a time-efficient measurement of the abundance and distribution of proteins within known supercomplexes. For complete details on the use and execution of this profile, please refer to Gonzalez-Franquesa et al. (2021).
    Keywords:  Mass Spectrometry; Metabolism; Protein Biochemistry; Proteomics
    DOI:  https://doi.org/10.1016/j.xpro.2022.101135
  12. Acta Pharm Sin B. 2022 Jan;12(1): 33-49
    Therapeutic regulation of autophagy in hepatic metabolism.
    Katherine Byrnes, Sophia Blessinger, Niani Tiaye Bailey, Russell Scaife, Gang Liu, Bilon Khambu.
      Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.
    Keywords:  AIM, Atf8 interacting motif; ATGL, adipose triglyceride lipase; ATL3, Atlastin GTPase 3; ATM, ATM serine/threonine kinase; Autophagy; BA, bile acid; BCL2L13, BCL2 like 13; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CAR, constitutive androstane receptor; CCPG1, cell cycle progression 1; CLN3, lysosomal/endosomal transmembrane protein; CMA, chaperonin mediated autophagy; CREB, cAMP response element binding protein; CRY1, cryptochrome 1; CYP27A1, sterol 27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; Cryptochrome 1; DFCP1, double FYVE-containing protein 1; FAM134B, family with sequence similarity 134, member B; FFA, free fatty acid; FOXO1, Forkhead box O1; FUNDC1, FUN14 domain containing 1; FXR, farnesoid X receptor; Farnesoid X receptor; GABARAPL1, GABA type A receptor associated protein like 1; GIM, GABARAP-interacting motif; LAAT-1, lysosomal amino acid transporter 1 homologue; LALP70, lysosomal apyrase-like protein of 70 kDa; LAMP1, lysosomal-associated membrane protein-1; LAMP2, lysosomal-associated membrane protein-2; LD, lipid droplet; LIMP1, lysosomal integral membrane protein-1; LIMP3, lysosomal integral membrane protein-3; LIR, LC3 interacting region; LXRa, liver X receptor a; LYAAT-1, lysosomal amino acid transporter 1; Liver metabolism; Lysosome; MCOLN1, mucolipin 1; MFSD1, major facilitator superfamily domain containing 1; NAFLD, non-alcoholic fatty liver disease; NBR1, BRCA1 gene 1 protein; NCoR1, nuclear receptor co-repressor 1; NDP52, calcium-binding and coiled-coil domain-containing protein 2; NPC-1, Niemann-Pick disease, type C1; Nutrient regeneration; OPTN, optineurin; PEX5, peroxisomal biogenesis factor 5; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PINK1, phosphatase and tensin homolog (PTEN)-induced kinase 1; PKA, protein kinase A; PKB, protein kinase B; PLIN2, perilipin 2; PLIN3, perilipin 3; PP2A, protein phosphatase 2a; PPARα, peroxisomal proliferator-activated receptor-alpha; PQLC2, PQ-loop protein; PXR, pregnane X receptor; Quality control; RETREG1, reticulophagy regulator 1; ROS, reactive oxygen species; RTN3, reticulon 3; RTNL3, a long isoform of RTN3; S1PR2, sphingosine-1-phosphate receptor 2; S6K, P70-S6 kinase; S6RP, S6 ribosomal protein; SCARB2, scavenger receptor class B member 2; SEC62, SEC62 homolog, preprotein translocation factor; SIRT1, sirtuin 1; SLC36A1, solute carrier family 36 member 1; SLC38A7, solute carrier family 38 member 7; SLC38A9, sodium-coupled neutral amino acid transporter 9; SNAT7, sodium-coupled neutral amino acid transporter 7; SPIN, spindling; SQSTM1, sequestosome 1; STBD1, starch-binding domain-containing protein 1; Signaling proteins; TBK1, serine/threonine-protein kinase; TEX264, testis expressed 264, ER-phagy receptor; TFEB/TFE3, transcription factor EB; TGR5, takeda G protein receptor 5; TRAC-1, thyroid-hormone-and retinoic acid-receptor associated co-repressor 1; TRPML1, transient receptor potential mucolipin 1; ULK1, Unc-51 like autophagy activating kinase 1; UPR, unfolded protein response; V-ATPase, vacuolar-ATPase; VDR, vitamin D3 receptor; VLDL, very-low-density lipoprotein; WIPI1, WD repeat domain phosphoinositide-interacting protein 1; mTORC1, mammalian target of rapamycin complex 1
    DOI:  https://doi.org/10.1016/j.apsb.2021.07.021
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