MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations

Rath, Sneha; Sharma, Rohit; Gupta, Rahul; Ast, Tslil; Chan, Connie H.; Durham, Timothy; Goodman, Rachel; Grabarek, Zenon; Haas, Mary E.; Hung, Wendy H. W.; Joshi, Pallavi; Jourdain, Alexis A.; Kim, Sharon; Kotrys, Anna V.; Lam, Stephanie S; McCoy, Jason G.; Meisel, Joshua D.; Miranda, María; Panda, Apekshya; Patgiri, Anupam; Rogers, Robert; Sadre, Shayan; Shah, Hardik; Skinner, Owen S.; To, Tsz Leung; Walker, Melissa; Wang, Hong; Ward, Patrick S.; Wengrod, Jordan; Yuan, Chen-Ching; Calvo, Sarah E.; Mootha, Vamsi K.

doi:10.1093/nar/gkaa1011

Cited by 1,068 publications

(974 citation statements)

References 34 publications

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“…In an effort to identify mitochondrial proteins that regulate OPA1 dynamics, we established an imaging-based screening pipeline to quantitatively assess the impact of all mitochondrial genes on mitochondrial morphology. To do this we coupled automated imaging and supervised ML mitochondrial morphology quantification workflow ( Figure 1A) with a bespoke siRNA library targeting 1531 known and putative nuclear-encoded mitochondrial genes (henceforth termed the Mitome siRNA library) generated based on publicly accessible databases of mitochondrial genes 36,37 (see Table S2 for gene list and plate distribution). This list is more extensive than MitoCarta 3.0 and also includes targets gene products whose function and localization have not yet been experimentally defined.…”

Section: High-throughput Screening Identifies Known and Novel Modifiementioning

confidence: 99%

High-throughput phenotypic screen for genetic modifiers in patient-derivedOPA1mutant fibroblasts identifiesPGS1as a functional suppressor of mitochondrial fragmentation

Cretin

Thomas

Vimont

et al. 2021

Preprint

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Mutations affecting the mitochondrial fusion protein Optic Atrophy 1 (OPA1) cause autosomal dominant optic atrophy (DOA) – one of the most common form of mitochondrial disease. The majority of patients develop isolated optic atrophy, but about 20% of OPA1 mutation carriers manifest more severe neurological deficits as part of a “DOA+” phenotype. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae organization, oxidative phosphorylation, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. To better understand the genetic regulation of mitochondrial dynamics, we established a high-throughput imaging pipeline using supervised machine learning (ML) to perform unbiased, quantitative mitochondrial morphology analysis that was coupled with a bespoke siRNA library targeting the entire known mitochondrial proteome (1531 genes), providing a detailed phenotypic screening of human fibroblasts. In control fibroblasts, we identified known and novel genes whose depletion promoted elongation or fragmentation of the mitochondrial network. In DOA+ patient fibroblasts, we identified 91 candidate genes whose depletion prevents mitochondrial fragmentation, including the mitochondrial fission genes DNM1L, MIEF1, and SLC25A46, but also genes not previously linked to mitochondrial dynamics such as Phosphatidyl Glycerophosphate Synthase (PGS1), which belongs to the cardiolipin (CL) synthesis pathway. PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation. This study illustrates the power of a first-in-kind objective automated imaging approach to uncover genetic modifiers of mitochondrial disease through high-throughput phenotypic screening of patient fibroblasts.

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Section: High-throughput Screening Identifies Known and Novel Modifiementioning

confidence: 99%

High-throughput phenotypic screen for genetic modifiers in patient-derivedOPA1mutant fibroblasts identifiesPGS1as a functional suppressor of mitochondrial fragmentation

Cretin

Thomas

Vimont

et al. 2021

Preprint

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“… Transcellular Mitophagy. Mitochondria are released at neuronal synapses where they are taken up by glial cells (astrocytes and/or microglia) for degradation [ 8 , 9 ]. Created with BioRender.com.…”

Section: Figurementioning

confidence: 99%

“…The mitochondrial inner membrane contains the ETC and ATP synthase enzymes and the mitochondrial matrix stores enzymes for the TCA cycle, mitochondrial DNA (mtDNA), and other crucial enzymes for protein folding and maintenance of pH gradients. For more detailed analysis of mitochondrial localized proteins MitoCarta3.0 was recently published [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Mitophagy and the Brain

Swerdlow

Wilkins

2020

IJMS

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Stress mechanisms have long been associated with neuronal loss and neurodegenerative diseases. The origin of cell stress and neuronal loss likely stems from multiple pathways. These include (but are not limited to) bioenergetic failure, neuroinflammation, and loss of proteostasis. Cells have adapted compensatory mechanisms to overcome stress and circumvent death. One mechanism is mitophagy. Mitophagy is a form of macroautophagy, were mitochondria and their contents are ubiquitinated, engulfed, and removed through lysosome degradation. Recent studies have implicated mitophagy dysregulation in several neurodegenerative diseases and clinical trials are underway which target mitophagy pathways. Here we review mitophagy pathways, the role of mitophagy in neurodegeneration, potential therapeutics, and the need for further study.

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“…Elsewhere NASA GeneLab ( 92 ) publishes in NAR for the first time and covers omics data obtained in space or simulated space conditions. Finally, MitoCarta, the popular focused resource for the mammalian mitochondrial proteome updates with curated sub-organelle localization and assignment of proteins to a set of 149 ‘MitoPathways’ ( 93 ).…”

Section: New and Updated Databasesmentioning

confidence: 99%

The 2021 Nucleic Acids Research database issue and the online molecular biology database collection

Rigden

Fernández

2020

Nucleic Acids Research

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The 2021 Nucleic Acids Research database Issue contains 189 papers spanning a wide range of biological fields and investigation. It includes 89 papers reporting on new databases and 90 covering recent changes to resources previously published in the Issue. A further ten are updates on databases most recently published elsewhere. Seven new databases focus on COVID-19 and SARS-CoV-2 and many others offer resources for studying the virus. Major returning nucleic acid databases include NONCODE, Rfam and RNAcentral. Protein family and domain databases include COG, Pfam, SMART and Panther. Protein structures are covered by RCSB PDB and dispersed proteins by PED and MobiDB. In metabolism and signalling, STRING, KEGG and WikiPathways are featured, along with returning KLIFS and new DKK and KinaseMD, all focused on kinases. IMG/M and IMG/VR update in the microbial and viral genome resources section, while human and model organism genomics resources include Flybase, Ensembl and UCSC Genome Browser. Cancer studies are covered by updates from canSAR and PINA, as well as newcomers CNCdatabase and Oncovar for cancer drivers. Plant comparative genomics is catered for by updates from Gramene and GreenPhylDB. The entire Database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). The NAR online Molecular Biology Database Collection has been substantially updated, revisiting nearly 1000 entries, adding 90 new resources and eliminating 86 obsolete databases, bringing the current total to 1641 databases. It is available at https://www.oxfordjournals.org/nar/database/c/.

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MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations

Cited by 1,068 publications

References 34 publications

High-throughput phenotypic screen for genetic modifiers in patient-derivedOPA1mutant fibroblasts identifiesPGS1as a functional suppressor of mitochondrial fragmentation

High-throughput phenotypic screen for genetic modifiers in patient-derivedOPA1mutant fibroblasts identifiesPGS1as a functional suppressor of mitochondrial fragmentation

Mitophagy and the Brain

The 2021 Nucleic Acids Research database issue and the online molecular biology database collection

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