Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

Morten Scheibye-Knudsen; Evandro Fei Fang; Deborah L. Croteau; Vilhelm A. Bohr

doi:10.4161/auto.29321

Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

Morten Scheibye-Knudsen, Evandro Fei Fang, Deborah L. Croteau, Vilhelm A. Bohr^*

^*Corresponding author af dette arbejde

30 Citationer (Scopus)

Abstract

DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

Originalsprog	Engelsk
Tidsskrift	Autophagy
Vol/bind	10
Udgave nummer	8
Sider (fra-til)	1468-1469
Antal sider	2
ISSN	1554-8627
DOI	https://doi.org/10.4161/auto.29321
Status	Udgivet - 2014
Udgivet eksternt	Ja

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.4161/auto.29321

auto.29321?needAccess=trueForlagets udgivne version, 1,31 MB

Andre filer og links

Link to publication in Scopus

Citationsformater

@article{de97504b42e74d2d8fb1636008490c2f,

title = "Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders",

abstract = "DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.",

keywords = "Autophagy, DNA repair, Mitophagy, SIRT1, Xeroderma pigmentosum group A",

author = "Morten Scheibye-Knudsen and Fang, {Evandro Fei} and Croteau, {Deborah L.} and Bohr, {Vilhelm A.}",

year = "2014",

doi = "10.4161/auto.29321",

language = "English",

volume = "10",

pages = "1468--1469",

journal = "Autophagy",

issn = "1554-8627",

publisher = "Taylor & Francis",

number = "8",

}

TY - JOUR

T1 - Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

AU - Scheibye-Knudsen, Morten

AU - Fang, Evandro Fei

AU - Croteau, Deborah L.

AU - Bohr, Vilhelm A.

PY - 2014

Y1 - 2014

N2 - DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

AB - DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

KW - Autophagy

KW - DNA repair

KW - Mitophagy

KW - SIRT1

KW - Xeroderma pigmentosum group A

UR - http://www.scopus.com/inward/record.url?scp=84905908997&partnerID=8YFLogxK

U2 - 10.4161/auto.29321

DO - 10.4161/auto.29321

M3 - Journal article

C2 - 24991831

AN - SCOPUS:84905908997

SN - 1554-8627

VL - 10

SP - 1468

EP - 1469

JO - Autophagy

JF - Autophagy

IS - 8

ER -

Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

Abstract

FN’s Verdensmål

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater