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Figure 3. (A) Representative transmission electron microscopy (TEM) images showing inner mitochondrial membrane (IMM) structures defects in U20S-stressed cells compared to untreated cells. Black arrows indicate IMM remodelling defects. Scale bars: 500 nm. (B) Representative N-Structured Illumination Microscopy (N-SIM) super-resolution image showing enlarged mitochondria and cytosolic mtDNA upon mitochondrial stress. Mitochondria and DNA were labelled using anti-TOM20 and anti-DNA antibodies, respectively. Scale bar: 2 um.

The mitochondrial genome consists of a single circular molecule that encodes 22 tRNAs and 13 protein subunits required for oxidative phosphorylation (OXPHOS) activity and adenosine triphosphate (ATP) production. Each mitochondrion contains multiple mtDNA copies that are bound to packaging proteins forming structures known as nucleoids. mtDNA copy number refers to the number of mitochondrial genomes per cell and is indicative of mitochondrial health [1]. It has been established that both mitochondrial fission and fusion processes are essential to ensure a proper mtDNA content along the mitochondrial network [2],[3],[4],[5]. Therefore, an adequate ratio of mitochondrial division and fusion events is essential to ensure mtDNA distribution, to avoid deleterious effects on mtDNA maintenance and to prevent the progression of diseases. However, the precise mechanisms by how mitochondrial morphology regulates mtDNA dynamics are not well understood.

In addition, recent discoveries have shown that not only nuclear or pathogen DNA can drive antiviral signaling and cellular inflammation, but also mitochondrial mtDNA. Similarly, to immunogenic bacterial DNA, mtDNA released in the cytosol is able to trigger different inflammatory responses. These signalling pathways were initially described in the cell death context, but recent studies have highlighted that other mitochondrial stresses including bacterial/viral infection, oxidative stress or mtDNA instability, were also able to induce mtDNA release in the cytosol triggering inflammation [6],[7].

We aim to elucidate how mitochondrial membrane remodelling (Figure 3A) regulates both mtDNA quality dynamics and the release of mtDNA in the cytosol (Figure 3B). To this purpose, we employ multiple in cellulo and in vivo models coupled to high-resolution microscopy methods to characterise new metabolic pathways and proteins involved in mtDNA dynamics and release, to elucidate how mitochondrial membrane dynamics control these phenomena and how these events are linked to cellular homeostasis.


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    Nat Rev Genet 22, 106-118. doi:10.1038/s41576-020-00284-x
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Group Members

Research support
   Mark Johnson
   Roy Chowdhury
   Goncalo de Castro Pereira
   Vincent Paupe
   Luis-Carlos Tabara Rodriguez
Post-graduate students
   Mayuko Segawa
   Filipa Santos Viegas
   Joe Ganellin
   Jara Villar