Thread by @jclandoni

So excited to finally share our paper, now available as a #bioRxiv preprint!

We found that enhancing #mtDNA replication can be highly deleterious, causing #Ferroptosis and neonatal 🫀#HeartDisease. 🧵thread coming soon..

biorxiv.org/content/10.110…

#newpublication #mitochondria

This project would not have been possible without the fantastic work from many people, so thank you all! @ASW_lab, @Kivela_lab, @WickstromLab, @JMitophile, @AWartiovaara et twitterless al.
@HelsinkiUniMed @helsinkiuni @HelsinkiUniMed @MitoResearch @uniofjyvaskyla @UniEastFinland

Recent years have brought several promising approaches to treat different kinds of #mitochondrial dysfunction, and increasing #mtDNA amount has been proposed to be beneficial for certain defects.

In contrast, our previous findings suggested that increased #mtDNA replication is actually the culprit of the "mitochondrial" premature #aging of the mtDNA mutator mouse (carrying a mutagenic mtDNA polymerase). Check out the paper for more details!
doi.org/10.1038/s42255…

So, we wondered 🤔 whether boosting #mtDNA replication (by overexpressing #Twinkle helicase) in mutators could be beneficial by increasing #mtDNA amount, or if it would instead accelerate the premature #aging phenotype...

biorxiv.org/content/10.110…

The answer: Neither.
Surprisingly, the overactive mtDNA replisome caused instead severe #mitochondrial #cardiomyopathy and growth defect shortly after birth.

biorxiv.org/content/10.110…

Although affected, #mtDNA integrity did not seem to be the main perpetrator. Instead, the replisome stress triggered a signaling cascade and disrupted the adaptation of cardiac #metabolism to oxidative postnatal life

biorxiv.org/content/10.110…

This cascade included the synergistic and dose-responsive interaction between the mitochondrial integrated stress response #ISRmt and key players in the #ferroptosis pathway

biorxiv.org/content/10.110…

Our findings indicate the need for caution when it comes to therapeutic approaches modulating #mtDNA amount, highlighting the importance of #mtDNA replication homeostasis in early #cardiac 🫀 life.

biorxiv.org/content/10.110…

The interesting link between cardiac maturation, #mtDNA replication, and the perinatal induction of #ISRmt + #ferroptosis hopefully also brings us a little closer to understanding these severe and complex defects.
biorxiv.org/content/10.110…

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