PXD023050-1

PXD023050 is an original dataset announced via ProteomeXchange.

Title	High levels of TFAM repress in vivo transcription of mitochondrial DNA
Description	Mammalian mitochondrial DNA (mtDNA) is coated with mitochondrial transcription factor A (TFAM) and compacted into nucleoids. TFAM is not only the main component of mitochondrial nucleoids but its levels can also control mtDNA copy number. Here we show that the TFAM-to-mtDNA ratio is critical for maintaining normal mtDNA expression in different tissues of the mouse. BAC transgenic mice with a 1.5-fold increase in TFAM protein levels maintain a normal TFAM-to-mtDNA ratio in different tissues and as a consequence mitochondrial gene expression, nucleoid distribution and whole animal metabolism are all unaltered. In contrast, mice expressing TFAM from the CAG promoter in the ROSA26 locus have 4.5-fold increase of TFAM protein levels in heart and skeletal muscle and develop pathology leading to early postnatal lethality. The TFAM-to-mtDNA ratio varies widely between tissues in these mice and is very high in skeletal muscle where it causes strong repression of mtDNA expression and deficient oxidative phosphorylation (OXPHOS) despite normal mtDNA levels. In heart, mtDNA copy number is increased leading to a near normal TFAM-to-mtDNA ratio and maintained OXPHOS capacity. In the liver, mtDNA expression is maintained despite increased TFAM levels and normal mtDNA levels. Here, tissue-specific induction of the LONP1 protease and mitochondrial RNA polymerase (POLRMT) expression counteracts the silencing effect of high TFAM levels. We conclude that the TFAM-to-mtDNA ratio has an important role in maintaining mtDNA expression in vivo. TFAM acts as a general repressor of mtDNA expression and this effect can be counterbalance by tissue-specific expression of regulatory factors.
HostingRepository	PRIDE
AnnounceDate	2021-08-18
AnnouncementXML	Submission_2021-08-18_04:49:47.586.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ilian Atanassov
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-10 06:36:40	ID requested
⏵ 1	2021-08-18 04:49:47	announced

Dataset with its publication pending

submitter keyword: TFAM, transcription, mitochondria, DNA, TMT

Nils-Göran Larsson
contact affiliation	Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden Max Planck Institute for Biology of Ageing–Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
contact email	nils-goran.larsson@ki.se
lab head
Ilian Atanassov
contact affiliation	Max Planck Institute for Biology of Aging
contact email	Ilian.Atanassov@age.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023050
     1. Label: PRIDE project
     2. Name: High levels of TFAM repress in vivo transcription of mitochondrial DNA