Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

Sen, Ayesha; Kallabis, Sebastian; Gaedke, Felix; Jungreuthmayer, Christian; Boix, Julia; Nüchel, Julian; Maliphol, Kanjanamas; Hofmann, Julia; Schauß, Astrid; Krüger, Marcus; Wiesner, Rudolf J.; Pla‐Martín, David

doi:10.1038/s41467-022-34205-9

Cited by 42 publications

(40 citation statements)

References 78 publications

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“…While VDAC and MICOS-MIB complexes were slightly increased, the prohibitin complex displayed a downward mass shift without a change in intensity. These observations likely depict the reorganization of mitochondrial membrane architecture in response to EtBr-induced stress and mtDNA depletion (74,75).…”

Section: Mitochondrial Gene Expression Rapidly Recovers After Removal...mentioning

confidence: 88%

Let’s make it clear: Systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling

Potter¹,

Cabrera‐Orefice

Spelbrink³

2023

Preprint

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Complexome profiling (CP) is a powerful tool for systematic investigation of protein interactors that has been primarily applied to study the composition and dynamics of mitochondrial protein complexes. Here, we further optimised this method to extend its application to survey mitochondrial DNA- and RNA-interacting protein complexes. We established that high-resolution clear native gel electrophoresis (hrCNE) is a better alternative to preserve DNA- and RNA-protein interactions that are otherwise disrupted when samples are separated by the widely used blue native gel electrophoresis (BNE). In combination with enzymatic digestion of DNA, our CP approach improved the identification of a wide range of protein interactors of the mitochondrial gene expression system without compromising the detection of other multi-protein complexes. The utility of this approach was particularly demonstrated by analysing the complexome changes in human mitochondria with impaired gene expression after transient, chemically-induced mtDNA depletion. Effects of RNase on mitochondrial protein complexes were also evaluated and discussed. Overall, our adaptations significantly improved the identification of mitochondrial DNA- and RNA-protein interactions by CP, thereby unlocking the comprehensive analysis of a near-complete mitochondrial complexome in a single experiment.

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Section: Mitochondrial Gene Expression Rapidly Recovers After Removal...mentioning

confidence: 88%

Let’s make it clear: Systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling

Potter¹,

Cabrera‐Orefice

Spelbrink³

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Also, several endosomal-dependent mitophagy pathways have recently been described, including studies involving vesicles positive for Rab5 38 , Rab7 48 , Rab11A 49 , or CARP2 50 . More recently, it has been reported that a component of the retromer responsible to transport select cargo between different endosomes, VPS35, is involved in an mtDNA-selective degradation process in conditions where mtDNA holds mutations 51 .…”

Section: Discussionmentioning

confidence: 99%

Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation

et al. 2023

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Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.

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“…ATAD3A is a conserved AAA+ ATPase that regulates mitochondrial inner membrane architecture. It spans the IMM with its C-terminus facing the matrix and associating with the nucleoids (Gilquin et al, 2010; Ishihara et al, 2022; Sen et al, 2022) (Figure S9A). We surmised that ATAD3A might link nucleoids comprising defective genomes with mitochondrial membranes.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial DNA Breaks Activate an Integrated Stress Response to Reestablish Homeostasis

Fu¹,

Kanshin

Ueberheide

et al. 2022

Preprint

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Mitochondrial DNA (mtDNA) breaks are deleterious lesions that lead to degradation of mitochondrial genomes and subsequent reduction in mtDNA copy number. The signaling pathways activated in response to mtDNA damage remain ill-defined. Using mitochondrial targeted restriction enzymes, we show that cells with mtDNA breaks exhibit reduced respiratory complexes, loss of membrane potential, and mitochondrial protein import defect. Furthermore, mtDNA damage activates the integrated stress response (ISR) through phosphorylation of eIF2α by the OMA1-DELE1-HRI pathway. Electron microscopy reveals concomitant defects in mitochondrial membranes and cristae ultrastructure. Notably, inhibition of the ISR exacerbates mitochondrial defects and delays the recovery of mtDNA copy number, thereby implicating this stress response in mitigating mitochondrial dysfunction following mtDNA damage. Last, we provide evidence suggesting that ATAD3A, a membrane-anchored protein that interacts with nucleoids, relays the signal from mtDNA breaks to the inner mitochondrial membrane. Altogether, our study fully delineates the sequence of events linking damaged mitochondrial genomes with the cytoplasm and uncovers an unanticipated role for the ISR in response to mitochondrial genome instability.

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Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

Cited by 42 publications

References 78 publications

Let’s make it clear: Systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling

Let’s make it clear: Systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling

Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation

Mitochondrial DNA Breaks Activate an Integrated Stress Response to Reestablish Homeostasis

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