SYSTEMS APPROACHES TO UNDERSTANDING MITOCHONDRIAL FUNCTION AND DYSFUNCTION IN DISEASE
Grant number: 1140851 | Funding period: 2018 - 2021
Mitochondria produce the energy for our bodies. Defects in this process cause mitochondrial disease, which affects at least 1/4300 people. Diagnosis is often inconclusive and few if any effective treatments exist. State of the art CRISPR gene-editing tools will be used to make disease models mimicking the different types of mitochondrial disease. These will be used to understand how mitochondria function, identify new disease genes and develop new drugs.
Related publications (31)
Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2.
Yeping Wu, Ye-Wheen Lim, David A Stroud, Nick Martel, Thomas E Hall, Harriet P Lo, Charles Ferguson, Michael T Ryan, Kerrie-Ann McMahon, Robert G Parton
Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole-cell proteom..
TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease.
Lindsey Van Haute, Emily O'Connor, Héctor Díaz-Maldonado, Benjamin Munro, Kiran Polavarapu, Daniella H Hock, Gautham Arunachal, Alkyoni Athanasiou-Fragkouli, Mainak Bardhan, Magalie Barth, Dominique Bonneau, Nicola Brunetti-Pierri, Gerarda Cappuccio, Nikeisha J Caruana, Natalia Dominik, Himanshu Goel, Guy Helman, Henry Houlden, Guy Lenaers, Karine Mention
Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired..
Investigation of oxidative phosphorylation activity and complex composition in mitochondrial disease.
Kyle Thompson, David A Stroud, David R Thorburn, Robert W Taylor
A multidisciplinary approach to the laboratory diagnosis of mitochondrial disease has long been applied, with crucial information ..
Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins
Michael D Healy, Joanna Sacharz, Kerrie E McNally, Calum McConville, Vikas A Tillu, Ryan J Hall, Molly Chilton, Peter J Cullen, Mehdi Mobli, Rajesh Ghai, David A Stroud, Brett M Collins
The sorting nexin SNX17 controls endosomal recycling of transmembrane cargo proteins including integrins, the amyloid precursor pr..
Two independent respiratory chains adapt OXPHOS performance to glycolytic switch
Erika Fernandez-Vizarra, Sandra Lopez-Calcerrada, Ana Sierra-Magro, Rafael Perez-Perez, Luke E Formosa, Daniella H Hock, Maria Illescas, Ana Penas, Michele Brischigliaro, Shujing Ding, Ian M Fearnley, Charalampos Tzoulis, Robert DS Pitceathly, Joaquin Arenas, Miguel A Martin, David A Stroud, Massimo Zeviani, Michael T Ryan, Cristina Ugalde
The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show t..
Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins
Allan Shuai Huang, Hui San Chin, Boris Reljic, Tirta M Djajawi, Iris KL Tan, Jia-Nan Gong, David A Stroud, David CS Huang, Mark F van Delft, Grant Dewson
Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to cont..
Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis
Chao Liang, Shan Zhang, David Robinson, Matthew Vander Ploeg, Rebecca Wilson, Jiemin Nah, Dale Taylor, Sheryl Beh, Radiance Lim, Lei Sun, Deborah M Muoio, David A Stroud, Lena Ho
Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Complex III (CIII)..
AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5
Silja Lucia Salscheider, Sarah Gerlich, Alfredo Cabrera-Orefice, Esra Peker, Robin Alexander Rothemann, Lena Maria Murschall, Yannik Finger, Karolina Szczepanowska, Zeinab Alsadat Ahmadi, Sergio Guerrero-Castillo, Alican Erdogan, Mark Becker, Muna Ali, Markus Habich, Carmelina Petrungaro, Nele Burdina, Guenter Schwarz, Merlin Klussmann, Ines Neundorf, David A Stroud
The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the impor..
Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module
Thomas D Jackson, Jordan J Crameri, Linden Muellner-Wong, Ann E Frazier, Catherine S Palmer, Luke E Formosa, Daniella H Hock, Kenji M Fujihara, Tegan Stait, Alice J Sharpe, David R Thorburn, Michael T Ryan, David A Stroud, Diana Stojanovski
SignificanceMitochondria are double-membraned eukaryotic organelles that house the proteins required for generation of ATP, the en..
Applying Sodium Carbonate Extraction Mass Spectrometry to Investigate Defects in the Mitochondrial Respiratory Chain
David RL Robinson, Daniella H Hock, Linden Muellner-Wong, Roopasingam Kugapreethan, Boris Reljic, Elliot E Surgenor, Carlos HM Rodrigues, Nikeisha J Caruana, David A Stroud
Mitochondria are complex organelles containing 13 proteins encoded by mitochondrial DNA and over 1,000 proteins encoded on nuclear..
Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly
Luke E Formosa, Shadi Maghool, Alice J Sharpe, Boris Reljic, Linden Muellner-Wong, David A Stroud, Michael T Ryan, Megan J Maher
Cytochrome c oxidase (COX) assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitocho..
High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content
Cesare Granata, Nikeisha J Caruana, Javier Botella, Nicholas A Jamnick, Kevin Huynh, Jujiao Kuang, Hans A Janssen, Boris Reljic, Natalie A Mellett, Adrienne Laskowski, Tegan L Stait, Ann E Frazier, Melinda T Coughlan, Peter J Meikle, David R Thorburn, David A Stroud, David J Bishop
Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible, inexpensive therapeutic i..
De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex
Kai-En Chen, Qian Guo, Timothy A Hill, Yi Cui, Amy K Kendall, Zhe Yang, Ryan J Hall, Michael D Healy, Joanna Sacharz, Suzanne J Norwood, Sachini Fonseka, Boyang Xie, Robert C Reid, Natalya Leneva, Robert G Parton, Rajesh Ghai, David A Stroud, David P Fairlie, Hiroaki Suga, Lauren P Jackson
The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer s..
Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response
Kerrie-Ann Mcmahon, David A Stroud, Yann Gambin, Vikas Tillu, Michele Bastiani, Emma Sierecki, Mark E Polinkovsky, Thomas E Hall, Guillermo A Gomez, Yeping Wu, Marie-Odile Parat, Nick Martel, Harriet P Lo, Kum Kum Khanna, Kirill Alexandrov, Roger Daly, Alpha Yap, Michael T Ryan, Robert G Parton
Caveolae-associated protein 3 (cavin3) is inactivated in most cancers. We characterized how cavin3 affects the cellular proteome u..
Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder
Nicole J Van Bergen, Sean Massey, Tegan Stait, Molly Ellery, Boris Reljic, Luke E Formosa, Anita Quigley, Mirella Dottori, David Thorburn, David A Stroud, John Christodoulou
CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the Cyclin-dependent kinase..
Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias
Rachel Thijssen, Sarah T Diepstraten, Donia Moujalled, Edward Chew, Christoffer Flensburg, Melissa X Shi, Michael A Dengler, Veronique Litalien, Sarah MacRaild, Maoshan Chen, Natasha S Anstee, Boris Reljic, Sarah S Gabriel, Tirta M Djajawi, Chris D Riffkin, Brandon J Aubrey, Catherine Chang, Lin Tai, Zhen Xu, Thomas Morley
Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemi..
Optic atrophy?associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I
Luke E Formosa, Boris Reljic, Alice J Sharpe, Daniella H Hock, Linden Muellner-Wong, David A Stroud, Michael T Ryan
Mitochondrial disease is a debilitating condition with a diverse genetic etiology. Here, we report that TMEM126A, a protein that i..
Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity
Cheryl QE Lee, Baptiste Kerouanton, Sonia Chothani, Shan Zhang, Ying Chen, Chinmay Kumar Mantri, Daniella Helena Hock, Radiance Lim, Rhea Nadkarni, Thang Huynh Vinh, Daryl Lim, Wei Leong Chew, Franklin L Zhong, David Arthur Stroud, Sebastian Schafer, Vinay Tergaonkar, Ashley L St John, Owen JL Rackham, Lena Ho
Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an ..
The TIM22 complex mediates the import of sideroflexins and is required for efficient mitochondrial one-carbon metabolism
Thomas D Jackson, Daniella H Hock, Kenji M Fujihara, Catherine S Palmer, Ann E Frazier, Yau C Low, Yilin Kang, Ching-Seng Ang, Nicholas J Clemons, David R Thorburn, David A Stroud, Diana Stojanovski
Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that contributes to protein biogenesis as a subunit of the TIM22 complex..
Fatal Perinatal Mitochondrial Cardiac Failure Caused by Recurrent De Novo Duplications in the ATAD3 Locus
Ann E Frazier, Alison G Compton, Yoshihito Kishita, Daniella H Hock, AnneMarie E Welch, Sumudu SC Amarasekera, Rocio Rius, Luke E Formosa, Atsuko Imai-Okazaki, David Francis, Min Wang, Nicole J Lake, Simone Tregoning, Jafar S Jabbari, Alexis Lucattini, Kazuhiro R Nitta, Akira Ohtake, Kei Murayama, David J Amor, George McGillivray
BACKGROUND: In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosi..
Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity
Justin P Hardee, Karen JB Martins, Paula M Miotto, James G Ryall, Stefan M Gehrig, Boris Reljic, Timur Naim, Jin D Chung, Jen Trieu, Kristy Swiderski, Ashleigh M Philp, Andrew Philp, Matthew J Watt, David A Stroud, Rene Koopman, Gregory R Steinberg, Gordon S Lynch
OBJECTIVES: Preferential damage to fast, glycolytic myofibers is common in many muscle-wasting diseases, including Duchenne muscul..
Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10
Guy Helman, Alison G Compton, Daniella H Hock, Marzena Walkiewicz, Gemma R Brett, Lynn Pais, Tiong Y Tan, Ricardo De Paoli-Iseppi, Michael B Clark, John Christodoulou, Susan M White, David R Thorburn, David A Stroud, Zornitza Stark, Cas Simons
The diagnosis of Mendelian disorders following uninformative exome and genome sequencing remains a challenging and often unmet nee..
Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome
Daniella H Hock, David RL Robinson, David A Stroud
Mitochondria produce the bulk of the energy used by almost all eukaryotic cells through oxidative phosphorylation (OXPHOS) which o..
Mutations in the exocyst component EXOC2 cause severe defects in human brain development
Nicole J Van Bergen, Syed Mukhtar Ahmed, Felicity Collins, Mark Cowley, Annalisa Vetro, Russell C Dale, Daniella H Hock, Christian de Caestecker, Minal Menezes, Sean Massey, Gladys Ho, Tiziana Pisano, Seana Glover, Jovanka Gusman, David A Stroud, Marcel Dinger, Renzo Guerrini, Ian G Macara, John Christodoulou
The exocyst, an octameric protein complex, is an essential component of the membrane transport machinery required for tethering an..
HIGD2A is Required for Assembly of the COX3 Module of Human Mitochondrial Complex IV
Daniella H Hock, Boris Reljic, Ching-Seng Ang, Linden Muellner-Wong, Hayley S Mountford, Alison G Compton, Michael T Ryan, David R Thorburn, David A Stroud
Assembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist in the..
Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly Complex Factors in the Biogenesis of Complex I
Luke E Formosa, Linden Muellner-Wong, Boris Reljic, Alice J Sharpe, Thomas D Jackson, Traude H Beilharz, Diana Stojanovski, Michael Lazarou, David A Stroud, Michael T Ryan
Mitochondrial complex I harbors 7 mitochondrial and 38 nuclear-encoded subunits. Its biogenesis requires the assembly and integrat..
Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly
Shan Zhang, Boris Reljic, Chao Liang, Baptiste Kerouanton, Joel Celio Francisco, Jih Hou Peh, Camille Mary, Narendra Suhas Jagannathan, Volodimir Olexiouk, Claire Tang, Gio Fidelito, Srikanth Nama, Ruey-Kuang Cheng, Caroline Lei Wee, Loo Chien Wang, Paula Duek Roggli, Prabha Sampath, Lydie Lane, Enrico Petretto, Radoslaw M Sobota
The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end ..
The Mitochondrial Acyl-carrier Protein Interaction Network Highlights Important Roles for LYRM Family Members in Complex I and Mitoribosome Assembly
Marris G Dibley, Luke E Formosa, Baobei Lyu, Boris Reljic, Dylan McGann, Linden Muellner-Wong, Felix Kraus, Alice J Sharpe, David A Stroud, Michael T Ryan
NDUFAB1 is the mitochondrial acyl carrier protein (ACP) essential for cell viability. Through its pantetheine-4'-phosphate post-tr..
Function of hTim8a in complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjaerg syndrome
Yilin Kang, Alexander J Anderson, Thomas Daniel Jackson, Catherine S Palmer, David P De Souza, Kenji M Fujihara, Tegan Stait, Ann E Frazier, Nicholas J Clemons, Deidreia Tull, David R Thorburn, Malcolm J McConville, Michael T Ryan, David A Stroud, Diana Stojanovski
Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in TIMM8A ..
Structural and functional characterization of the mitochondrial complex IV assembly factor Coa6
Shadi Maghool, N Dinesha G Cooray, David A Stroud, David Aragao, Michael T Ryan, Megan J Maher
Assembly factors play key roles in the biogenesis of many multi-subunit protein complexes regulating their stability, activity, an..
OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect
Kyle Thompson, Nicole Mai, Monika Olahova, Filippo Scialo, Luke E Formosa, David A Stroud, Madeleine Garrett, Nichola Z Lax, Fiona M Robertson, Cristina Jou, Andres Nascimento, Carlos Ortez, Cecilia Jimenez-Mallebrera, Steven A Hardy, Langping He, Garry K Brown, Paula Marttinen, Robert McFarland, Alberto Sanz, Brendan J Battersby
OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative ..