Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability
- 19 January 2021
- journal article
- research article
- Published by Taylor & Francis Ltd in Autophagy
- Vol. 17 (11), 3444-3460
- https://doi.org/10.1080/15548627.2021.1874209
Abstract
Genotoxic insult causes nuclear and mitochondrial DNA damages with macroautophagy/autophagy induction. The role of mitochondrial DNA (mtDNA) damage in the requirement of autophagy for nuclear DNA (nDNA) stability is unclear. Using site-specific DNA damage approaches, we show that specific nDNA damage alone does not require autophagy for repair unless in the presence of mtDNA damage. We provide evidence that after IR exposure-induced mtDNA and nDNA damages, autophagy suppression causes non-apoptotic mitochondrial permeability, by which mitochondrial ENDOG (endonuclease G) is released and translocated to nuclei to sustain nDNA damage in a TET (tet methylcytosine dioxygenase)-dependent manner. Furthermore, blocking lysosome function is sufficient to increase the amount of mtDNA leakage to the cytosol, accompanied by ENDOG-free mitochondrial puncta formation with concurrent ENDOG nuclear accumulation. We proposed that autophagy eliminates the mitochondria specified by mtDNA damage-driven mitochondrial permeability to prevent ENDOG-mediated genome instability. Finally, we showed that HBx, a hepatitis B viral protein capable of suppressing autophagy, also causes mitochondrial permeability-dependent ENDOG mis-localization in nuclei and is linked to hepatitis B virus (HBV)-mediated hepatocellular carcinoma development. Abbreviations: 3-MA: 3-methyladenine; 5-hmC: 5-hydroxymethylcytosine; ACTB: actin beta; ATG5: autophagy related 5; ATM: ATM serine/threonine kinase; DFFB/CAD: DNA fragmentation factor subunit beta; cmtDNA: cytosolic mitochondrial DNA; ConA: concanamycin A; CQ: chloroquine; CsA: cyclosporin A; Dox: doxycycline; DSB: double-strand break; ENDOG: endonuclease G; GFP: green fluorescent protein; Gy: gray; H2AX: H2A.X variant histone; HBV: hepatitis B virus; HBx: hepatitis B virus X protein; HCC: hepatocellular carcinoma; I-PpoI: intron-encoded endonuclease; IR: ionizing radiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOMP: mitochondrial outer membrane permeability; mPTP: mitochondrial permeability transition pore; mtDNA: mitochondrial DNA; nDNA: nuclear DNA; 4-OHT: 4-hydroxytamoxifen; rDNA: ribosomal DNA; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TET: tet methylcytosine dioxygenase; TFAM: transcription factor A, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; VDAC: voltage dependent anion channel.Keywords
Funding Information
- College of Medicine, National Taiwan University (NTU-109L901402D)
- Ministry of Science and Technology, Taiwan (MOST 109-2326-B-002-004)
- Ministry of Science and Technology, Taiwan (MOST 109-2634-F-002-043)
This publication has 49 references indexed in Scilit:
- The mitochondrial permeability transition pore: a mystery solved?Frontiers in Physiology, 2013
- Dynamics of the Degradation of Ubiquitinated Proteins by Proteasomes and AutophagyOnline Journal of Public Health Informatics, 2011
- Apoptosis: it's BAK to VDACEMBO Reports, 2009
- Control of mitochondrial apoptosis by the Bcl-2 familyJournal of Cell Science, 2009
- The Atg12-Atg5 Conjugate Has a Novel E3-like Activity for Protein Lipidation in AutophagyJournal of Biological Chemistry, 2007
- The Mitochondrial Transcription Factor TFAM Coordinates the Assembly of Multiple DNA Molecules into Nucleoid-like StructuresMolecular Biology of the Cell, 2007
- Autophagy suppresses tumor progression by limiting chromosomal instabilityGenes & Development, 2007
- Switch from Caspase-dependent to Caspase-independent Death during Heart DevelopmentOnline Journal of Public Health Informatics, 2006
- Blocking of G1/S transition and cell death in the regenerating liver of Hepatitis B virus X protein transgenic miceBiochemical and Biophysical Research Communications, 2006
- Early nuclear translocation of endonuclease G and subsequent DNA fragmentation after transient focal cerebral ischemia in miceNeuroscience Letters, 2005