ORCID Profile
0000-0002-4402-945X
Current Organisation
Walter and Eliza Hall Institute of Medical Research
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Publisher: Wiley
Date: 15-03-2011
DOI: 10.1016/J.FEBSLET.2011.03.022
Abstract: The Saccharomyces cerevisiae MEF2 gene is a mitochondrial protein translation factor. Formerly believed to catalyze peptide elongation, evidence now suggests its involvement in ribosome recycling. This study confirms the role of the MEF2 gene for cell respiration and further uncovers a slow growth phenotype and reduced chronological lifespan. Furthermore, in comparison with cytoplasmic ρ(0) strains, mef2Δ strains have a marked reduction of the inner mitochondrial membrane potential and mitochondria show a tendency to aggregate, suggesting an additional role for the MEF2 gene in maintenance of mitochondrial health, a role that may also be shared by other mitochondrial protein synthesis factors.
Publisher: Wiley
Date: 13-11-2020
Publisher: Springer Science and Business Media LLC
Date: 15-03-2022
Publisher: Springer Science and Business Media LLC
Date: 21-12-2022
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JMB.2019.05.015
Abstract: Mitochondrial membrane proteins with internal targeting signals are inserted into the inner membrane by the carrier translocase (TIM22 complex). For this, precursors have to be initially directed from the TOM complex in the outer mitochondrial membrane across the intermembrane space toward the TIM22 complex. How these two translocation processes are topologically coordinated is still unresolved. Using proteomic approaches, we find that the human TIM22 complex associates with the mitochondrial contact site and cristae organizing system (MICOS) complex. This association does not appear to be conserved in yeast, whereby the yeast MICOS complex instead interacts with the presequence translocase. Using a yeast mic10Δ strain and a HEK293T MIC10 knockout cell line, we characterize the role of MICOS for protein import into the mitochondrial inner membrane and matrix. We find that a physiological cristae organization promotes efficient import via the presequence pathway in yeast, while in human mitochondria, the MICOS complex is dispensable for protein import along the presequence pathway. However, in human mitochondria, the MICOS complex is required for the efficient import of carrier proteins into the mitochondrial inner membrane. Our analyses suggest that in human mitochondria, positioning of the carrier translocase at the crista junction, and potentially in vicinity to the TOM complex, is required for efficient transport into the inner membrane.
Publisher: American Society for Cell Biology (ASCB)
Date: 04-2022
Abstract: Using a combination of techniques (mass spectrometry, BN–PAGE, immunodetection, and mitochondrial in vitro import assays), it is reported that a previously poorly described protein, OCIAD2, localizes to the inner mitochondrial membrane and participates in the formation of electron transport chain complexes.
Publisher: Public Library of Science (PLoS)
Date: 14-06-2012
Publisher: Cold Spring Harbor Laboratory
Date: 09-08-2023
DOI: 10.1101/2023.08.08.552531
Abstract: PINK1 is a ubiquitin kinase that accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson’s disease. Nucleotide analogues such as kinetin triphosphate (KTP) have been suggested to enhance PINK1 activity and may represent a therapeutic strategy for the treatment of Parkinson’s disease. Here, we investigate the interaction of PINK1 with nucleotides, including KTP. We establish a cryo-EM platform exploiting the previously observed dodecamer assembly of Pediculus humanus corporis ( Ph ) PINK1 to determine PINK1 structures bound to AMP-PNP and ADP, which reveal unexpected conformational changes in the kinase N-lobe to enable PINK1 to form a ubiquitin binding site. Strikingly, we find that KTP is unable to bind Ph PINK1 or human ( Hs ) PINK1 due to a steric clash with the kinase ‘gatekeeper’ residue. Mutation of the gatekeeper to Ala or Gly is required to enable PINK1 to bind and utilise KTP as a phosphate donor in ubiquitin phosphorylation and mitophagy. Indeed, Hs PINK1 M318G can be used to conditionally uncouple PINK1 stabilisation and activity on mitochondria.
Publisher: Portland Press Ltd.
Date: 21-03-2022
DOI: 10.1042/BST20211107
Abstract: Parkinson's disease is a neurodegenerative disorder characterised by cardinal motor symptoms and a erse range of non-motor disorders in patients. Parkinson's disease is the fastest growing neurodegenerative condition and was described for the first time over 200 years ago, yet there are still no reliable diagnostic markers and there are only treatments that temporarily alleviate symptoms in patients. Early-onset Parkinson's disease is often linked to defects in specific genes, including PINK1 and Parkin, that encode proteins involved in mitophagy, the process of selective autophagic elimination of damaged mitochondria. Impaired mitophagy has been associated with sporadic Parkinson's and agents that damage mitochondria are known to induce Parkinson's-like motor symptoms in humans and animal models. Thus, modulating mitophagy pathways may be an avenue to treat a subset of early-onset Parkinson's disease that may additionally provide therapeutic opportunities in sporadic disease. The PINK1/Parkin mitophagy pathway, as well as alternative mitophagy pathways controlled by BNIP3L/Nix and FUNDC1, are emerging targets to enhance mitophagy to treat Parkinson's disease. In this review, we report the current state of the art of mitophagy-targeted therapeutics and discuss the approaches being used to overcome existing limitations to develop innovative new therapies for Parkinson's disease. Key approaches include the use of engineered mouse models that harbour pathogenic mutations, which will aid in the preclinical development of agents that can modulate mitophagy. Furthermore, the recent development of chimeric molecules (AUTACs) that can bypass mitophagy pathways to eliminate damaged mitochondria thorough selective autophagy offer new opportunities.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Oxford University Press (OUP)
Date: 03-2010
DOI: 10.1111/J.1567-1364.2009.00593.X
Abstract: Statins, used to treat hypercholesterolemia, are one of the most frequently prescribed drug classes in the developed world. However, a significant proportion of users suffer symptoms of myotoxicity, and currently, the molecular mechanisms underlying myotoxicity remain ambiguous. In this study, Saccharomyces cerevisiae was exploited as a model system to gain further insight into the molecular mechanisms of atorvastatin toxicity. Atorvastatin-treated yeast cells display marked morphological deformities, have reduced cell viability and are highly vulnerable to perturbed mitochondrial function. Supplementation assays of atorvastatin-treated cells reveal that both loss of viability and mitochondrial dysfunction occur as a consequence of perturbation of the sterol synthesis pathway. This was further investigated by supplementing statin-treated cells with various metabolites of the sterol synthesis pathway that are believed to be essential for cell function. Ergosterol, coenzyme Q and a heme precursor were all ineffective in the prevention of statin-induced mitochondrial disruption and cell death. However, the addition of geranylgeranyl pyrophosphate and farnesyl pyrophosphate significantly restored cell viability, although these did not overcome petite induction. This highlights the pleiotropic nature of statin toxicity, but has established protein prenylation disruption as one of the principal mechanisms underlying statin-induced cell death in yeast.
Publisher: Walter de Gruyter GmbH
Date: 09-03-2020
Abstract: Mitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation. Initially, the precursors pass the outer membrane through the TOM complex and are handed over to the TIM23 complex where they are sorted into the inner membrane or translocated into the matrix. This handover process depends on the receptor proteins at the inner membrane, Tim50 and Tim23, which are critical for efficient import. In this review, we summarize key findings that shaped the current concepts of protein translocation along the presequence import pathway, with a particular focus on the precursor handover process from TOM to the TIM23 complex. In addition, we discuss functions of the human TIM23 pathway and the recently uncovered pathogenic mutations in TIM50.
Publisher: EMBO
Date: 23-12-2015
Abstract: Barth syndrome ( BTHS ) is a cardiomyopathy caused by the loss of tafazzin, a mitochondrial acyltransferase involved in the maturation of the glycerophospholipid cardiolipin. It has remained enigmatic as to why a systemic loss of cardiolipin leads to cardiomyopathy. Using a genetic ablation of tafazzin function in the BTHS mouse model, we identified severe structural changes in respiratory chain supercomplexes at a pre‐onset stage of the disease. This reorganization of supercomplexes was specific to cardiac tissue and could be recapitulated in cardiomyocytes derived from BTHS patients. Moreover, our analyses demonstrate a cardiac‐specific loss of succinate dehydrogenase ( SDH ), an enzyme linking the respiratory chain with the tricarboxylic acid cycle. As a similar defect of SDH is apparent in patient cell‐derived cardiomyocytes, we conclude that these defects represent a molecular basis for the cardiac pathology in Barth syndrome.
Publisher: Oxford University Press (OUP)
Date: 04-09-2018
DOI: 10.1093/HMG/DDY305
Publisher: Springer Science and Business Media LLC
Date: 05-2019
Publisher: Wiley
Date: 26-10-2016
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.BBAMCR.2021.119133
Abstract: The respiratory chain, embedded in the inner mitochondrial membrane, is organized as a network of in idual complexes, as well as large supercomplex structures. In the yeast S. cerevisiae, these supercomplexes consist of a dimeric cytochrome bc
Publisher: Elsevier BV
Date: 11-2010
Publisher: Frontiers Media SA
Date: 28-03-2018
Publisher: Frontiers Media SA
Date: 19-05-2022
Publisher: Elsevier BV
Date: 02-2018
Location: Australia
Location: Germany
No related grants have been discovered for Sylvie Callegari.