The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization

He, Jin; Mao, Chih-Chieh; Reyes, Aurelio; Sembongi, Hiroshi; Re, Miriam Di; Granycome, Caroline; Clippingdale, Andrew B.; Fearnley, Ian M.; Harbour, Michael E.; Robinson, Alan J.; Reichelt, Stefanie; Spelbrink, Johannes N.; Walker, John E.; Holt, Ian

doi:10.1083/jcb.200609158

Cited by 201 publications

(240 citation statements)

References 27 publications

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“…Two proteins have been implicated in this process, but it remains a largely unexplored area of mitochondrial biology. One of the proteins, ATAD3, is particularly intriguing, as it was found in enriched preparations of mtDNA and its amino-terminal part has a remarkable preference for binding to DNA structures with a triple-stranded section (D-loop) [22]. Furthermore, gene silencing of ATAD3 induces topological changes in mtDNA, and there appears to be an inverse correlation between nucleoid size and ATAD3 abundance [52].…”

Section: The Machinery Of Mtdna Selectionmentioning

confidence: 99%

“…However, this might be only part of the explanation (see also [8]). If mtDNA is either always membrane attached, as suggested by its resistance to alkaline stripping [22], or solely during replication [23], then DNA architecture and topology for an 11 kb molecule will be different from a 16 kb molecule. In particular, the amount of twisting is likely to be greater for the shorter mtDNA.…”

Section: Selection Of Mitochondrial Dnas Via a Direct Replicative Advmentioning

confidence: 99%

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The road to rack and ruin: selecting deleterious mitochondrial DNA variants

Holt¹,

Speijer

Kirkwood

2014

Phil. Trans. R. Soc. B

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Mitochondria constitute the major energy-producing compartment of the eukaryotic cell. These organelles contain many molecules of DNA that contribute only a handful of proteins required for energy production. Mutations in the DNA of mitochondria were identified as a cause of human disease a quarter of a century ago, and they have subsequently been implicated in ageing. The process whereby deleterious variants come to dominate a cell, tissue or human is the subject of debate. It is likely to involve multiple, often competing, factors, as selection pressures on mitochondrial DNA can be both indirect and intermittent, and are subjected to rapid change. Here, we assess the different models and the prospects for preventing the accumulation of deleterious mitochondrial DNA variants with time.

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Section: The Machinery Of Mtdna Selectionmentioning

confidence: 99%

Section: Selection Of Mitochondrial Dnas Via a Direct Replicative Advmentioning

confidence: 99%

The road to rack and ruin: selecting deleterious mitochondrial DNA variants

Holt¹,

Speijer

Kirkwood

2014

Phil. Trans. R. Soc. B

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“…The mtDNA helicase Twinkle might also affect D-loop structures (Korhonen et al 2003). Moreover, a D-loop-stabilizing protein has also been reported (He et al 2007). These observations suggest that the D-loop could be important for transcription because it can effect a rapid transition in DNA conformation.…”

Section: Activity Of Polrmtmentioning

confidence: 99%

DNA conformation‐dependent activities of human mitochondrial RNA polymerase

et al. 2009

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Mitochondrial RNA polymerase (POLRMT) is a core protein for mitochondrial DNA (mtDNA) transcription. In addition, POLRMT is assumed to be involved in replication, although its exact role is not yet clearly elucidated. We have found novel properties of human POLRMT using a reconstituted transcription system. Various lengths of RNA molecules were synthesized from templates even without a defined promoter sequence, when we used supercoiled circular doublestranded DNA as a template. This promoter-independent activity was as strong as the promoterdependent one. Promoter-independent DNA conformation-dependent transcription required TFB2M. On supercoiled templates, the promoter-independent activity was strongly suppressed by a putatively physiological amount of TFAM, while promoter-dependent transcription was inhibited to a lesser extent. These different inhibition patterns by TFAM may be important for prevention of random RNA synthesis in vivo. Promoter-independent activity was also observed on relaxed circular single-stranded DNA, where its activity no longer required TFB2M. RNA synthesis on single-stranded DNA was weakly suppressed by a putatively physiological amount of TFAM but restored by the addition of mitochondrial single-stranded DNA binding protein.We suggest that these properties of POLRMT could explain the characteristic features of mammalian mtDNA transcription and replication.

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“…mtDNA is physically associated with the mitochondrial inner membrane in DNA-protein complexes known as nucleoids (19,20), and a disturbance in this association is known to disrupt mtDNA-encoded gene expression. Thus, given the aberrant cristae morphology of UCP1-KO BAT mitochondria after exposure to 4°C (Fig.…”

Section: Significancementioning

confidence: 99%

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

Kazak

Chouchani

Stavrovskaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

145

107

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Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Δp) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance. UCP1-deficient BAT mitochondria exhibit reduced mitochondrial calcium buffering capacity and are highly sensitive to mitochondrial permeability transition induced by reactive oxygen species (ROS) and calcium overload. This dysfunction depends on ROS production by reverse electron transport through mitochondrial complex I, and can be rescued by inhibition of electron transfer through complex I or pharmacologic depletion of ROS levels. Our findings indicate that the interscapular BAT of Ucp1 knockout mice exhibits mitochondrial disruptions that extend well beyond the deletion of UCP1 itself. This finding should be carefully considered when using this mouse model to examine the role of UCP1 in physiology.brown fat | mitochondria | ROS | UCP1 | electron transport chain U ncoupling protein 1 (UCP1) plays a role in acute adaptive thermogenesis in interscapular brown adipose tissue (BAT). UCP1 dissipates the mitochondrial protonmotive force (Δp) generated by the electron transport chain (ETC) and is important for thermal homeostasis in rodents and human infants (1, 2). Ucp1 orthologs are not limited to mammals, but are also expressed in ectothermic vertebrates (3) and protoendothermic mammals (4), suggesting that UCP1 may have an important role in biology beyond thermal control. For example, it is becoming increasingly evident that in specific respiratory states, UCP1 can reduce reactive oxygen species (ROS) levels in vitro (4-9). The mitochondrial ETC is a major source of ROS production in the cell, and ROS play important roles in physiology and pathophysiology (10-12). Reverse electron transport (RET) through mitochondrial complex I is a key mechanism by which ROS are generated in vivo (11, 13). Interestingly, RET relies critically on high Δp, whereas dissipation of Δp by UCP1 can lower ROS levels in isolated mitochondria (5-7).Thermogenic respiration in BAT is triggered by external stimuli that activate adrenergic signaling (14). Most notably, environmental cold induces the capacity for adrenergic-mediated BAT respiration in wild type (WT) animals, but only minimally in UCP1-KO animals (15, 16). It is understood that the respiratory response of BAT under these conditions is indicative of UCP1-mediated respiration; however, the rate of maximal chemically uncoupled oxygen consumption, an UCP1-independent parameter, is also lower in UCP1-KO adipocytes compared with WT (15, 16).Moreover, the basal respiratory rat...

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The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization

Cited by 201 publications

References 27 publications

The road to rack and ruin: selecting deleterious mitochondrial DNA variants

The road to rack and ruin: selecting deleterious mitochondrial DNA variants

DNA conformation‐dependent activities of human mitochondrial RNA polymerase

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

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