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MRC Mitochondrial Biology Unit

 

Alex Whitworth

MRC Investigator

 

 

 

 

Mitochondria in neurodegeneration: Investigating the role of mitochondria and metabolism in the cause and therapeutic targeting of neurodegenerative diseases

The survival of our most active tissues, such as the brain and heart, throughout decades of a human lifespan presents an extraordinary biological challenge. Mitochondria are central to the life and death of these tissues. While providing the high amount of energy required by these cells and buffering cytoplasmic calcium flux, they also produce many of the molecules that cause cellular damage and house a lethal arsenal of apoptotic cell death machinery. Thus, these organelles require extensive maintenance and quality control processes. Failure in mitochondrial homeostasis is strongly linked to age-related conditions such as neurodegeneration.

To perform the myriad essential cellular roles in complex cells such as neurons mitochondria must be extremely dynamic. They are transported large distances to respond to localised demands for energy and calcium buffering, and undergo frequent fission and fusion events with each other and other organelles.

The long-lived post-mitotic nature of adult neurons permits the accumulation of oxidatively damaged macromolecules, and mitochondria are particularly susceptible. To combat this, mitochondria have multiple quality control mechanisms to recognise and remove potentially destructive aberrant components. However, much of our current understanding comes from in vitro studies, so we still have a poor understanding of this process in a physiological context.

Our group aims to understand the mechanisms of mitochondrial homeostasis in relation to neurodegenerative diseases such as Parkinson’s disease and motor neuron disease. We use a combination of the powerful genetic techniques of Drosophila and molecular, cell biology and biochemical approaches in mammalian cells. Insights into these mechanisms will deliver a greater understanding of the role of mitochondrial maintenance in the health and dysfunction of the nervous system in a physiological context and will help guide therapeutic development to combat neurodegenerative diseases.

 

Biography

Alex Whitworth obtained a BSc at Imperial College London (1997) and a PhD (2001) at the University of Cambridge, studying the genetic control of development in Drosophila. He then joined Prof. Leo Pallanck at the University of Washington as a post-doctoral fellow, where they developed several new Drosophila models of Parkinson's disease (PD). In 2005 he started his own research group at the University of Sheffield as Lecturer, progressing to Senior Lecturer (2010) and Reader (2013), being and ERC Starting Grant awardee in 2012. In 2015 he joined the MRC Mitochondrial Biology Unit as a Programme Leader.

Publications

Selected Publications

Castelli LM, Cutillo L, Souza CDS, Sanchez-Martinez A, Granata I, Lin YH, Myszczynska MA, Heath PR, Livesey MR, Ning K, Azzouz M, Shaw PJ, Guarracino MR, Whitworth AJ, Ferraiuolo L, Milo M & Hautbergue GM (2021)
SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis
Mol Neurodegener 16, 53

Terriente-Felix A, Wilson EL, Whitworth AJ (2020)
Drosophila phosphatidylinositol-4 kinase fwd promotes mitochondrial fission and can suppress Pink1/parkin phenotypes
PLoS Genet 16, e1008844

Andreazza S, Samstag CL, Sanchez-Martinez A, Fernandez-Vizarra E, Gomez-Duran A, Lee JJ, Tufi R, Hipp MJ, Schmidt EK, Nicholls TJ, Gammage PA, Chinnery PF, Minczuk M, Pallanck LJ, Kennedy SR, Whitworth AJ (2019)
Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila
Nat Commun 10, 3280

Tufi R, Gleeson TP, von Stockum S, Hewitt VL, Lee JJ, Terriente-Felix A, Sanchez-Martinez A, Ziviani E, Whitworth AJ (2019)
Comprehensive genetic characterization of mitochondrial Ca2+ uniporter components reveals their different physiological requirements in vivo
Cell Rep 27, 1541-1550.e5

Schöndorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, Giunta I, Schwarz LK, Di Napoli G, Panagiotakopoulou V, Nestel S, Keatinge M, Pruszak J, Bandmann O, Heimrich B, Gasser T, Whitworth AJ & Deleidi M (2018)
The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson's disease.
Cell Rep 23, 2976-2988

Lee JJ, Sanchez-Martinez A, Zarate AMartinez, Benincá C, Mayor U, Clague MJ & Whitworth AJ (2018)
Basal mitophagy is widespread inbut minimally affected by loss of Pink1 or parkin.
J Cell Biol 217, 1613-1622

Publication profile - Google Scholar

PubMed (last 10 years)

 

Group Members

Research Support
   Ana Terriente-Felix
Post-docs
   Federica De Lazzari
   Aitor Martinez Zarate
   Leonor Miller-Fleming
   Alvaro Sanchez-Martinez
Post-graduate students
   Wing Hei Au
   Ha Yoon Cho
   Madeleine Twyning

Contacts

Email

Tel: +44(0)1223 252910