期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep15292
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资金
- Academy of Finland [258065, 252048]
- Netherlands Organization for Scientific Research [865.10.004]
- EMBO ALTF [1066-2011]
- Estonian Research Council [PUT610, IUT14021]
- European Research Council [260632]
- Medical Research Council
- Sigrid Juselius Foundation
- Medicinska Understodsforeningen Liv och Halsa
- Magnus Ehrnrooth foundation
- Academy of Finland (AKA) [258065, 258065] Funding Source: Academy of Finland (AKA)
- European Research Council (ERC) [260632] Funding Source: European Research Council (ERC)
- Medical Research Council [MC_U105663140] Funding Source: researchfish
- MRC [MC_U105663140] Funding Source: UKRI
The helicase Twinkle is indispensable for mtDNA replication in nucleoids. Previously, we showed that Twinkle is tightly membrane-associated even in the absence of mtDNA, which suggests that Twinkle is part of a membrane-attached replication platform. Here we show that this platform is a cholesterol-rich membrane structure. We fractionated mitochondrial membrane preparations on flotation gradients and show that membrane-associated nucleoids accumulate at the top of the gradient. This fraction was shown to be highly enriched in cholesterol, a lipid that is otherwise low abundant in mitochondria. In contrast, more common mitochondrial lipids, and abundant inner-membrane associated proteins concentrated in the bottom-half of these gradients. Gene silencing of ATAD3, a protein with proposed functions related to nucleoid and mitochondrial cholesterol homeostasis, modified the distribution of cholesterol and nucleoids in the gradient in an identical fashion. Both cholesterol and ATAD3 were previously shown to be enriched in ER-mitochondrial junctions, and we detect nucleoid components in biochemical isolates of these structures. Our data suggest an uncommon membrane composition that accommodates platforms for replicating mtDNA, and reconcile apparently disparate functions of ATAD3. We suggest that mtDNA replication platforms are organized in connection with ER-mitochondrial junctions, facilitated by a specialized membrane architecture involving mitochondrial cholesterol.
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