bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021‒05‒30
nine papers selected by
Nicoletta Plotegher
University of Padua

  1. Autophagy. 2021 May 26.
      The sensu stricto autophagy, macroautophagy, is considered to be both a metabolic process as well as a bona fide quality control process. The question as to how these two aspects of autophagy are coordinated and whether and why they overlap has implications for fundamental aspects, pathophysiological effects, and pharmacological manipulation of autophagy. At the top of the regulatory cascade controlling autophagy are master regulators of cellular metabolism, such as MTOR and AMPK, which render the system responsive to amino acid and glucose starvation. At the other end exists a variety of specific autophagy receptors, engaged in the selective removal of a diverse array of intracellular targets, from protein aggregates/condensates to whole organelles such as mitochondria, ER, peroxisomes, lysosomes and lipid droplets. Are the roles of autophagy in metabolism and quality control mutually exclusive, independent or interlocked? How are priorities established? What are the molecular links between both phenomena? This article will provide a starting point to formulate these questions, the responses to which should be taken into consideration in future autophagy-based interventions.
    Keywords:  AMPK; ATG; Aging; Akt; Alzheimer’s disease; ESCRT; FOXO; LC3; MTOR; NAD; NASH; Obesity; Parkinson’s Disease; RagA/B; SIRT1; SIRT3; Selective autophagy; TBK1; TCA; TFEB; Tor; acetyl CoA; autophagy; calcienurin; cancer; cardiovascular; diabetes; endoplasmic reticulum; fatty acids; ferritin; galectin; glycogen; glycolysis; heart; immunity; infection; insulin; lipid droplets; liver; lysosomes; metabolism; mitochondria; mitophagy; neurodegeneration; nutrition; oxidative phosphorylation; p62 SQSTM1; peroxisome; quality control; sirtuin
  2. Methods Mol Biol. 2021 ;2322 81-92
      The physiological importance of mitochondrial quality control has been uncovered by the finding that genes for early onset Parkinson's disease (PD), PINK1 and Parkin, regulate mitochondrial autophagy, called mitophagy, and motility. Dopaminergic neurons derived from human-induced pluripotent stem (iPS) cells are a useful tool for analyzing the pathogenesis caused by defects in mitochondrial quality control and for screening candidate drugs for PD. Moreover, dopaminergic neurons could provide new findings not obtained in other cells. In this chapter, we will describe our method for monitoring PINK1-Parkin signaling using iPS cell-derived dopaminergic neurons.
    Keywords:  Autophagy; Dopaminergic neuron; Immunocytochemistry; Mitochondria; PINK1; Parkin; Ubiquitin; Western blot; iPS cells
  3. Autophagy. 2021 May 24. 1-23
      Parkinson disease (PD)-affected brains show consistent endoplasmic reticulum (ER) stress and mitophagic dysfunctions. The mechanisms underlying these perturbations and how they are directly linked remain a matter of questions. XBP1 is a transcription factor activated upon ER stress after unconventional splicing by the nuclease ERN1/IREα thereby yielding XBP1s, whereas PINK1 is a kinase considered as the sensor of mitochondrial physiology and a master gatekeeper of mitophagy process. We showed that XBP1s transactivates PINK1 in human cells, primary cultured neurons and mice brain, and triggered a pro-mitophagic phenotype that was fully dependent of endogenous PINK1. We also unraveled a PINK1-dependent phosphorylation of XBP1s that conditioned its nuclear localization and thereby, governed its transcriptional activity. PINK1-induced XBP1s phosphorylation occurred at residues reminiscent of, and correlated to, those phosphorylated in substantia nigra of sporadic PD-affected brains. Overall, our study delineated a functional loop between XBP1s and PINK1 governing mitophagy that was disrupted in PD condition.Abbreviations: 6OHDA: 6-hydroxydopamine; baf: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CCCP: carbonyl cyanide chlorophenylhydrazone; COX8A: cytochrome c oxidase subunit 8A; DDIT3/CHOP: DNA damage inducible transcript 3; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FACS: fluorescence-activated cell sorting; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFN2: mitofusin 2; OPTN: optineurin; PD: Parkinson disease; PINK1: PTEN-induced kinase 1; PCR: polymerase chain reaction:; PRKN: parkin RBR E3 ubiquitin protein ligase; XBP1s [p-S61A]: XBP1s phosphorylated at serine 61; XBP1s [p-T48A]: XBP1s phosphorylated at threonine 48; shRNA: short hairpin RNA, SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TM: tunicamycin; TMRM: tetramethyl rhodamine methylester; TOMM20: translocase of outer mitochondrial membrane 20; Toy: toyocamycin; TP: thapsigargin; UB: ubiquitin; UB (S65): ubiquitin phosphorylated at serine 65; UPR: unfolded protein response, XBP1: X-box binding protein 1; XBP1s: spliced X-box binding protein 1.
    Keywords:  Mitophagy; PINK1; Parkinson disease; XBP1; phosphorylation; transcription; unfolded protein response
  4. FASEB J. 2021 Jun;35(6): e21620
      Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides, they play an active role in calcium and damage-associated molecular patterns signaling, amino acid, and lipid metabolism, and apoptosis. Thus, the maintenance of mitochondrial integrity and homeostasis is extremely critical, which is achieved through continual fusion and fission. Mitochondrial fusion allows the transfer of gene products between mitochondria for optimal functioning, especially under metabolic and environmental stress. On the other hand, fission is crucial for mitochondrial division and quality control. The imbalance between these two processes is associated with various ailments such as cancer, neurodegenerative and cardiovascular diseases. This review discusses the molecular mechanisms that control mitochondrial fusion and fission and how the disruption of mitochondrial dynamics manifests into various disease conditions.
    Keywords:  diseases; dynamics; fission; fusion; mitochondria
  5. Cell. 2021 May 27. pii: S0092-8674(21)00530-4. [Epub ahead of print]184(11): 2896-2910.e13
      Damaged mitochondria need to be cleared to maintain the quality of the mitochondrial pool. Here, we report mitocytosis, a migrasome-mediated mitochondrial quality-control process. We found that, upon exposure to mild mitochondrial stresses, damaged mitochondria are transported into migrasomes and subsequently disposed of from migrating cells. Mechanistically, mitocytosis requires positioning of damaged mitochondria at the cell periphery, which occurs because damaged mitochondria avoid binding to inward motor proteins. Functionally, mitocytosis plays an important role in maintaining mitochondrial quality. Enhanced mitocytosis protects cells from mitochondrial stressor-induced loss of mitochondrial membrane potential (MMP) and mitochondrial respiration; conversely, blocking mitocytosis causes loss of MMP and mitochondrial respiration under normal conditions. Physiologically, we demonstrate that mitocytosis is required for maintaining MMP and viability in neutrophils in vivo. We propose that mitocytosis is an important mitochondrial quality-control process in migrating cells, which couples mitochondrial homeostasis with cell migration.
    Keywords:  migrasome; mitochondrial quality control; mitochondrion; mitocytosis; mitosome
  6. J Cell Sci. 2021 May 26. pii: jcs.253781. [Epub ahead of print]
      In Saccharomyces cerevisiae, the selective autophagic degradation of mitochondria, termed mitophagy, is critically regulated by the adapter protein, Atg32. Despite our knowledge about the molecular mechanisms by which Atg32 controls mitophagy, its physiological roles in yeast survival and fitness remains less clear. Here, we demonstrate a requirement for Atg32 in promoting spermidine production during respiratory growth and heat-induced mitochondrial stress. During respiratory growth, mitophagy-deficient yeast exhibit profound heat-stress induced defects in growth and viability due to impaired biosynthesis of spermidine and its biosynthetic precursor S-Adenosyl-Methionine (SAM). Moreover, spermidine production is crucial for the induction of cytoprotective nitric oxide (NO) during heat stress. Hence, the re-addition of spermidine to Atg32 mutant yeast is sufficient to both enhance NO production and restore respiratory growth during heat stress. Our findings uncover a previously unrecognized physiological role for yeast mitophagy in spermidine metabolism and illuminate new interconnections between mitophagy, polyamine biosynthesis and NO signaling.
    Keywords:  ATG32; Autophagy; Mitophagy; Nitric Oxide; S-Adenosyl-Methionine; Spermidine
  7. J Cell Biol. 2021 Aug 02. pii: e202009092. [Epub ahead of print]220(8):
      Mitophagy is the degradation of surplus or damaged mitochondria by autophagy. In addition to programmed and stress-induced mitophagy, basal mitophagy processes exert organelle quality control. Here, we show that the sorting and assembly machinery (SAM) complex protein SAMM50 interacts directly with ATG8 family proteins and p62/SQSTM1 to act as a receptor for a basal mitophagy of components of the SAM and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 regulates mitochondrial architecture by controlling formation and assembly of the MICOS complex decisive for normal cristae morphology and exerts quality control of MICOS components. To this end, SAMM50 recruits ATG8 family proteins through a canonical LIR motif and interacts with p62/SQSTM1 to mediate basal mitophagy of SAM and MICOS components. Upon metabolic switch to oxidative phosphorylation, SAMM50 and p62 cooperate to mediate efficient mitophagy.
  8. Biochem J. 2021 May 28. 478(10): 1977-1984
      Underground early development of higher plants includes two distinct developmental processes, seed germination and then skotomorphogenesis, a mechanism which favours elongation of the hypocotyl and helps the seedling to find light. Interestingly, both processes, which are regulated by plant hormones, have been shown to depend on reactive oxygen species metabolism and to be related to mitochondrial retrograde signalling. Here we review the recent outcomes in this field of research and highlight the emerging role of ROS communication between organelles and cell compartments. We point out the role of mitochondria as an environmental and developmental sensor organelle that regulates ROS homeostasis and downstream events and we propose future directions of research that should help better understanding the roles of ROS in germination and seedling emergence.
    Keywords:  germination; mitochondria; plant signal transduction; reactive oxygen species; skotomorphogenesis
  9. Prog Mol Subcell Biol. 2021 ;59 99-114
      The endoplasmic reticulum (ER) is a biosynthetic organelle in eukaryotic cells. Its capacity to produce proteins, lipids and oligosaccharides responds to physiologic and pathologic demand. The transcriptional and translational unfolded protein response (UPR) programs increase ER size and activity. In contrast, ER-phagy programs in all their flavors select ER subdomains for lysosomal clearance. These programs are activated by nutrient deprivation, accumulation of excess ER (recov-ER-phagy), production of misfolded proteins that cannot be degraded by ER-associated degradation and that are removed from cells by the so-called ER-to-lysosome-associated degradation (ERLAD). Selection of ER subdomains to be cleared from cells relies on ER-phagy receptors, a class of membrane-bound proteins displaying cytosolic domains that engage the cytosolic ubiquitin-like protein LC3. Mechanistically, ER clearance proceeds via macro-ER-phagy, micro-ER-phagy and LC3-regulated vesicular delivery.
    Keywords:  Autophagy; ER-phagy receptors; ERLAD; Endoplasmic reticulum; LC3; Macro-ER-phagy and micro-ER-phagy; Vesicular transport