Mike Murphy

Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease | NEJM Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuc...

It was wonderful to see the NEJM paper today about healthy babies born free of mtDNA disease following mitochondrial donation. Built on decades of work led by Doug Turnbull and his team in Newcastle.

www.nejm.org/doi/full/10....

It was a great pleasure to attend last week Professor Dunja Aksentijevic's inaugural Professorial Lecture at Queen Mary, University of London. Dunja, it's just the start!

Enhancing autophagy by redox regulation extends lifespan in Drosophila - Nature Communications Redox signalling is emerging as an important regulator of metabolism and physiology, which is dysregulated in ageing and disease. Here, the authors show that redox regulation of a key redox sensitive ...

Congrats to Helena Cocheme @cochemelab.bsky.social on her paper on redox regulation of autophagy in Drosophila.
doi.org/10.1038/s414...

Good day yesterday at the William Harvey Research Institute Research Day where I was honoured to receive the Derek Willoughby Medal and give a lecture. Great hospitality from Dunja Aksentijevic and Sir Mark Caulfield.

Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis - Nature Communications Clonal hematopoiesis is driven by the selective advantage of mutant hematopoietic stem cells. Here, authors discover that elevated mitochondrial activity is a targetable mechanism by which mutant hema...

doi.org/10.1038/s414...

Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs - Nature Dnmt3a mutations in mouse haematopoietic stem and progenitor cells equivalent to R882 mutations in human cause increased mitochondrial respiration, suggesting that this is a mechanism of clonal h...

doi.org/10.1038/s415...

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis - Nature Metformin may serve as a non-toxic intervention to inhibit mitochondrial metabolism and slow DNMT3A-R882 clonal haematopoiesis expansion, thus delaying or averting progression to acute myeloid le...

Series of interesting papers showing that haematopoietic stem cells can undergo damaging clonal haematopoiesis when they acquire mutations that enhance mitochondrial respiration - opening the way to using metformin - and my beloved MitoQ - to prevent this transition.

doi.org/10.1038/s415...

Congrats to Dunja Aksienijevic on her latest paper!

By the Atlantic in Galway at the SFRRI meeting - catching up with old friends and new.

www.sfrrgalway2025.com

Shows convincingly that that obesity increases mitochondrial ROS by RET in the liver in vivo to drive insulin resistance. This is proposed to be due to defects in CoQ biosynthesis - some fascinating findings here that will take time to explore by the community.

CoQ imbalance drives reverse electron transport to disrupt liver metabolism - Nature Reverse electron transport is the mechanism behind excess mitochondrial reactive oxygen species in the livers of obese mice, which has implications for developing therapeutics for fatty liver dis...

Congrats to Renata Goncalves who led a study in Gokhan Hotamisligil's lab that has just come out in Nature - ably assisted by Jillian Riveros!

www.nature.com/articles/s41...

Congratulations to Abigail Giles who was awarded the "The Richard J. Bing Award for Young Investigators" at the recent World Congress of the International Society For Heart Research in Japan.

Well done Abigail!

Congratulations to @clarebryant.bsky.social on her election to the Academy of Medical Sciences!

Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise | American Journal of Physiology-Heart and Circulatory Physiology | American Physiological Socie... Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes, however, the underlying mechanisms are not fully understood. This s...

Congrats to Ana Vujic on her latest paper!

journals.physiology.org/doi/abs/10.1...

CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition - Nature Communications CREBBP mutations in B-cell acute lymphoblastic leukemia (B-ALL) are linked to poor prognosis and chemoresistance. Here, the authors show that genetic or pharmacological inactivation of CREBBP sensitiz...

Delighted to be a small part of this paper led by Alicia, Brian and Simon.

doi.org/10.1038/s414...

CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition - Nature Communications CREBBP mutations in B-cell acute lymphoblastic leukemia (B-ALL) are linked to poor prognosis and chemoresistance. Here, the authors show that genetic or pharmacological inactivation of CREBBP sensitiz...

Delighted that our work describing a potential novel treatment approach for B-cell Acute Lymphoblastic Leukaemia is published today in @natcomms.nature.com‬. 🧵

www.nature.com/articles/s41...

Pleased to have been elected a Member of Academia Europaea. Thanks to Mike Davies of Copenhagen for nominating me.

www.ae-info.org/ae/Member/Mu...

IMS-MRL External Seminar (Cambridge)
Tuesday 6 May 2025 at 13.15

Professor Mike Murphy,

Understanding how mitochondria contribute to ischaemia-reperfusion injury

HOST: Professor Steve O’Rahilly

Hybrid Seminar in the IMS-MRL Seminar Rooms (for IMS staff), Online for others

At the University of Cordoba today giving a seminar in the department of Prof Raquel Requejo. She used to be post-doc in my lab in Cambridge and is now running her own lab.

www.uco.es/dptos/bioqui...

Visiting IBIS in beautiful Sevilla www.ibis-sevilla.es/en/
Hosted by José López-Barneo - giving a seminar there today.

Sleep pressure accumulates in a voltage-gated lipid peroxidation memory - Nature Sleep-inducing neurons in Drosophila rely on Hyperkinetic, the β-subunit of the KV1 channel Shaker, to monitor sleep need by translating lipid peroxidation events into changes in the oxidation state o...

Important new paper in Nature from Gero Miesenböck's lab showing that the accumulation of lipid peroxidation products from mitochondrial ROS production leads in sleep.

doi.org/10.1038/s415...

Pretzel Therapeutics Initiates Phase 1 Clinical Study Evaluating PX578, Lead Therapeutic in its Bioenergetics Restoration Franchise » Pretzel Therapeutics First-in-class approach to targeting mitochondrial DNA polymerase (POLG) with disease modifying potential across mitochondrial DNA depletion syndromes

Congrats to Michal Minczuk @mitogene.bsky.social and all at Pretzel Therapeutics on initiation of their first Phase I trial!

www.pretzeltx.com/pretzel-ther...

FEBS Press O2 sensing by carotid body chemoreceptor cells depends on mitochondrial complex I (MCI) function. In mice with a mutated ND6 subunit, which retains normal forward MCI activity but cannot catalyze rev...

Well done to María Torres-López and José López-Barneo on this paper in FEBS Letts - seems that RET at complex I is not involved in carotid body oxygen sensing...

doi.org/10.1002/1873...

TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition TRAM–LAG1–CLN8 family proteins function as enzymes that remodel cellular phospholipids and expand the membrane lipid diversity.

Congrats to Kasparas Petkevicius on his paper just out in Science Advances - Andrew James in my lab played a key role - important implications for Battens Disease

doi.org/10.1126/scia...

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation - Nature Metabolism Casey et al. explore the basic mechanisms of mitochondrial superoxide production and its impact on interleukin-1β production in LPS-treated macrophages.

Great to see paper from Alva Casey out today in Nature Metabolism - from her PhD.
Well done Alva!

doi.org/10.1038/s422...

Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation Petrovic et al. demonstrate that ergothioneine acts as an alternative substrate for cystathionine gamma-lyase, an H2S-producing enzyme, leading to an increase of protein persulfidation. The persulfida...

Glad to be a small part on this interesting paper from Milos Filipovic with actual work done by Jan Miljkovic and Alva Casey in my lab.

Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation: Cell Metabolism www.cell.com/cell-metabol...

It will also be interesting to see the enzymology of the short chain RQ analogue with UQ enzymes. The source of the putative in vivo RQ (diet? microbiome? endogenous?) will also be good to explore.

I suspect some of these may be due to the enhanced antioxidant effects of RQ cf. UQ. With the findings of RQ in tissues I’m intrigued as the levels reported are very high. Moreover, the quantification was done by LC/MS not LC-MS/MS vs an internal standard. In my view this needs to be revisited.

Regarding paper in Cell from Jessica Spinelli on rhodoquinone (RQ) in mammalian mitochondria. The implication is that the lower reduction potential will allow SDH to run to fumarate more easily under hypoxic conditions. The introduction of RQ in vivo was elegant and gave pharmacological effects.

Rhodoquinone carries electrons in the mammalian electron transport chain Valeros et al. identify rhodoquinone (RQ), an electron carrier present in mammalian mitochondria, that can deliver electrons to fumarate instead of O2 as the terminal electron acceptor. The authors de...

Very interesting paper in Cell from Jessica Spinelli showing rhodoquinone (RQ) in mammalian mitochondria. www.cell.com/cell/fulltex...