ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription

Chuan Yang Dai; Chai Chee Ng; Grace Ching Ching Hung; Ina Kirmes; Laetitia A. Hughes; Yunguang Du; Christopher A. Brosnan; Arnaud Ahier; Anne Hahn; Cole M. Haynes; Oliver Rackham; Aleksandra Filipovska; Steven Zuryn

doi:10.1038/s41556-023-01192-y

ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription

Chuan Yang Dai, Chai Chee Ng, Grace Ching Ching Hung, Ina Kirmes, Laetitia A. Hughes, Yunguang Du, Christopher A. Brosnan, Arnaud Ahier, Anne Hahn, Cole M. Haynes, Oliver Rackham, Aleksandra Filipovska, Steven Zuryn

UWA Centre for Medical Research (affiliated with the Harry Perkins Institute of Medical Research)
UWA Centre for Child Health Research (affiliated with the The Kids Research Institute Australia)

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete¹, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. ^2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.

Original language	English
Pages (from-to)	1111-1120
Number of pages	10
Journal	Nature Cell Biology
Volume	25
Issue number	8
DOIs	https://doi.org/10.1038/s41556-023-01192-y
Publication status	Published - 17 Jul 2023

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10.1038/s41556-023-01192-y

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@article{92a4f3ac0eac451ba8d03d697123c48c,

title = "ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription",

abstract = "The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.",

author = "Dai, {Chuan Yang} and Ng, {Chai Chee} and Hung, {Grace Ching Ching} and Ina Kirmes and Hughes, {Laetitia A.} and Yunguang Du and Brosnan, {Christopher A.} and Arnaud Ahier and Anne Hahn and Haynes, {Cole M.} and Oliver Rackham and Aleksandra Filipovska and Steven Zuryn",

note = "Funding Information: We thank R. Tweedale, M. Hilliard and V. Anggono for the comments on the paper and members of the Zuryn laboratory for discussions and comments. This work was supported by NHMRC project grants GNT1128381 and GNT1162553 (to S.Z.), GNT2010332 (to A.F. and O.R.), ARC Discovery grant DP200101630 (to S.Z.), a Clem Jones Centre for Ageing Dementia flagship grant (to S.Z.), a Stafford Fox senior research fellowship (to S.Z.), NHMRC fellowships APP1154646 (to A.F.) and APP1154932 (to O.R.), University of Queensland International Scholarships to C.-Y.D. and C.-C.N., and a DFG postdoctoral fellowship to I.K. A.F. and O.R. are investigators of the ARC Centre of Excellence in Synthetic Biology (CE200100029). Funding Information: The genotypes of all transgenic animals generated for this study are presented in Supplementary Table . The universal MosSCI strains EG8078, EG8079, EG8080 and EG8081, as well as the mutant strains RB877, nth-1(ok724) III; VC2626, twnk-1(ok3198) X; SS104, glp-4(bn2) I; RW1596, myo-3(st386) V; stEx30[myo-3p::GFP::myo-3 + rol-6 (su1006)]; SJ4100, zcIs13[hsp-6p::GFP + lin-15(+)] V; SJ4058, zcIs9[hsp-60::GFP] V; SJ4005, zcIs4[hsp-4::GFP] V; and CL2070, dvIs70[hsp-16.2p::GFP + rol-6(su1006)], were obtained from the Caenorhabditis Genetics Center (Minneapolis, MN, United States), which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). The strains atfs-1(tm4525) V; and atfs-1(tm4919) V were obtained from the National BioResource Project (Tokyo, Japan). Unless otherwise noted, atfs-1 indicates the tm4525 allele in all figures. The transgene Is[myo-3p::GFP] in SJZ1040 was crossed from strain IR1284, Is[myo-3p::GFP]; Ex[lgg-1p::DsRed::lgg-1] which was a gift from N. Tavernarakis (IMBB-FoRTH, Heraklion, Greece). The strain SJZ33, foxSi2[myo-3p::TOMM-20::RFP] was generated in a previous study, as were SJZ819, fox28[mrps-12(K89T)], SJZ820, fox29[mrps-12(K90I)] (ref. ), atfs-1(cmh15) (ref. ) and atfs-1 (ref. ). The strain PHX041, sybIs135[atfs-1p::atfs-1::GFP + odr-1p::GFP] was generated by SunyBiotech (Fuzhou, Fujian, China). C. elegans were handled using standard methods. −/− mt mt MTS nuc mit Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = jul,

day = "17",

doi = "10.1038/s41556-023-01192-y",

language = "English",

volume = "25",

pages = "1111--1120",

journal = "Nature Cell Biology",

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T1 - ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription

AU - Dai, Chuan Yang

AU - Ng, Chai Chee

AU - Hung, Grace Ching Ching

AU - Kirmes, Ina

AU - Hughes, Laetitia A.

AU - Du, Yunguang

AU - Brosnan, Christopher A.

AU - Ahier, Arnaud

AU - Hahn, Anne

AU - Haynes, Cole M.

AU - Rackham, Oliver

AU - Filipovska, Aleksandra

AU - Zuryn, Steven

N1 - Funding Information: We thank R. Tweedale, M. Hilliard and V. Anggono for the comments on the paper and members of the Zuryn laboratory for discussions and comments. This work was supported by NHMRC project grants GNT1128381 and GNT1162553 (to S.Z.), GNT2010332 (to A.F. and O.R.), ARC Discovery grant DP200101630 (to S.Z.), a Clem Jones Centre for Ageing Dementia flagship grant (to S.Z.), a Stafford Fox senior research fellowship (to S.Z.), NHMRC fellowships APP1154646 (to A.F.) and APP1154932 (to O.R.), University of Queensland International Scholarships to C.-Y.D. and C.-C.N., and a DFG postdoctoral fellowship to I.K. A.F. and O.R. are investigators of the ARC Centre of Excellence in Synthetic Biology (CE200100029). Funding Information: The genotypes of all transgenic animals generated for this study are presented in Supplementary Table . The universal MosSCI strains EG8078, EG8079, EG8080 and EG8081, as well as the mutant strains RB877, nth-1(ok724) III; VC2626, twnk-1(ok3198) X; SS104, glp-4(bn2) I; RW1596, myo-3(st386) V; stEx30[myo-3p::GFP::myo-3 + rol-6 (su1006)]; SJ4100, zcIs13[hsp-6p::GFP + lin-15(+)] V; SJ4058, zcIs9[hsp-60::GFP] V; SJ4005, zcIs4[hsp-4::GFP] V; and CL2070, dvIs70[hsp-16.2p::GFP + rol-6(su1006)], were obtained from the Caenorhabditis Genetics Center (Minneapolis, MN, United States), which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). The strains atfs-1(tm4525) V; and atfs-1(tm4919) V were obtained from the National BioResource Project (Tokyo, Japan). Unless otherwise noted, atfs-1 indicates the tm4525 allele in all figures. The transgene Is[myo-3p::GFP] in SJZ1040 was crossed from strain IR1284, Is[myo-3p::GFP]; Ex[lgg-1p::DsRed::lgg-1] which was a gift from N. Tavernarakis (IMBB-FoRTH, Heraklion, Greece). The strain SJZ33, foxSi2[myo-3p::TOMM-20::RFP] was generated in a previous study, as were SJZ819, fox28[mrps-12(K89T)], SJZ820, fox29[mrps-12(K90I)] (ref. ), atfs-1(cmh15) (ref. ) and atfs-1 (ref. ). The strain PHX041, sybIs135[atfs-1p::atfs-1::GFP + odr-1p::GFP] was generated by SunyBiotech (Fuzhou, Fujian, China). C. elegans were handled using standard methods. −/− mt mt MTS nuc mit Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/7/17

Y1 - 2023/7/17

N2 - The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.

AB - The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.

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U2 - 10.1038/s41556-023-01192-y

DO - 10.1038/s41556-023-01192-y

M3 - Article

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AN - SCOPUS:85164964209

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VL - 25

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JO - Nature Cell Biology

JF - Nature Cell Biology

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ER -

ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription

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ARC Centre of Excellence in Synthetic Biology

Designing new therapeutics using medical synthetic biology

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ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription

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ARC Centre of Excellence in Synthetic Biology

Designing new therapeutics using medical synthetic biology

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