Inactivation of cardiolipin synthase triggers changes in mitochondrial morphology

Matsumura, Ayaka; Higuchi, Jiro; Watanabe, Yasunori; Kato, Masahiro; Aoki, Kimiya; Akabane, Shiori; Endo, Toshiya; Oka, Toshihiko

doi:10.1002/1873-3468.12948

Cited by 21 publications

(15 citation statements)

References 37 publications

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“…The dynamic network of mitochondria can meet the energy and metabolic needs of cells. The intracellular mitochondrial morphology network represents a perfect balance between the fusion/fission events [ 24 ]. Mitochondrial dynamics is mainly regulated by Drp1, mitofusin (Mfn) 1 and Mfn2, and other mitochondrial fusion and fission-related proteins [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Increased Mitochondrial Fragmentation Mediated by Dynamin-Related Protein 1 Contributes to Hexavalent Chromium-Induced Mitochondrial Respiratory Chain Complex I-Dependent Cytotoxicity

Ma¹,

Zhou²,

Xiao³

et al. 2020

Toxics

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Hexavalent chromium (Cr(VI)) pollution is a severe public health problem in the world. Although it is believed that mitochondrial fragmentation is a common phenomenon in apoptosis, whether excessive fission is crucial for apoptosis remains controversial. We previously confirmed that Cr(VI) mainly targeted mitochondrial respiratory chain complex I (MRCC I) to induce reactive oxygen species (ROS)-mediated apoptosis, but the related mechanism was unclear. In this study, we found Cr(VI) targeted MRCC I to induce ROS accumulation and triggered mitochondria-related cytotoxicity. Cr(VI)-induced cytotoxicity was alleviated by pretreatment of Glutamate/malate (Glu/Mal; MRCC I substrates), and was aggravated by cotreatment of rotenone (ROT; MRCC I inhibitor). Cr(VI) induced excessive mitochondrial fragmentation and mitochondrial dynamin-related protein 1 (Drp1) translocation, the application of Drp1-siRNA alleviated Cr(VI)-induced apoptosis. The cytotoxicity in the Drp1-si plus Cr(VI) treatment group was alleviated by the application of Glu/Mal, and was aggravated by the application of ROT. Drp1 siRNA promoted the inhibition of Glu/Mal on Cr(VI)-induced cytotoxicity, and alleviated the aggravation of ROT on Cr(VI)-induced cytotoxicity. Taken together, Cr(VI)-induced Drp1 modulation was dependent on MRCC I inhibition-mediated ROS production, and Drp1-mediated mitochondrial fragmentation contributed to Cr(VI)-induced MRCC I-dependent cytotoxicity, which provided the experimental basis for further elucidating Cr(VI)-induced cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

Increased Mitochondrial Fragmentation Mediated by Dynamin-Related Protein 1 Contributes to Hexavalent Chromium-Induced Mitochondrial Respiratory Chain Complex I-Dependent Cytotoxicity

Ma¹,

Zhou²,

Xiao³

et al. 2020

Toxics

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“…We know, for example, that the accumulation of PG compromises the barrier function of the inner mitochondrial membrane in pgc1Δ cells (Pokorná et al, 2015). In C. elegans, changes in mitochondrial morphology triggered after inactivation of CL synthase were recently also interpreted in terms of PG accumulation rather than lack of CL (Matsumura et al, 2018). Also, it is worth mentioning that the product of PG hydrolysis, DAG, is an important signaling molecule (Roelants et al, 2017;Stahelin et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The lipid droplet protein Pgc1 controls the subcellular distribution of phosphatidylglycerol

Kubalová

Veselá

Awadová

et al. 2018

Preprint

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The biosynthesis of yeast phosphatidylglycerol (PG) takes place in the inner mitochondrial membrane. Outside mitochondria, the abundance of PG is low. Here we present evidence that the subcellular distribution of PG is maintained by locally controlled enzymatic activity of the PGspecific phospholipase, Pgc1. We document that the Pgc1 absence leads to spreading of PG over various cellular membranes. Fluorescently labeled Pgc1 protein strongly accumulates at the surface of lipid droplets (LD). We show, however, that LD are not only dispensable for Pgc1mediated PG degradation, but even host no phospholipase activity of Pgc1. Our in vitro assays document the capability of LD-accumulated Pgc1 to degrade PG upon entry to membranes of the endoplasmic reticulum, mitochondria, and even of artificial phospholipid vesicles. FRAP analysis confirms continuous exchange of GFP-Pgc1 within individual LD in situ, suggesting that a steady-state equilibrium exists between LD and membranes to regulate immediate phospholipase activity of Pgc1. In this model, LD serve as storage place and shelter Pgc1 preventing untimely degradation, while both phospholipase activity and degradation of the enzyme occur in membranes.

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“…Second, WT MEFs depleted of either Pgs1 or Tamm41 show reduced CL levels similar to Opa1 Crispr MEFs but without an induction of mitochondrial fragmentation ( Figure 5B, C). Third, inhibition of cardiolipin synthase (Cls1) does not cause mitochondrial fragmentation but rather promotes mitochondrial elongation ( Figure 5B) 75 . Fourth, depletion of the CL remodeling enzyme Tafazzin (TAZ1), does not impair mitochondrial fusion nor trigger mitochondrial fragmentation 76 .…”

Section: Opa1 Crispr Pgs1 Crisprmentioning

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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Inactivation of cardiolipin synthase triggers changes in mitochondrial morphology

Cited by 21 publications

References 37 publications

Increased Mitochondrial Fragmentation Mediated by Dynamin-Related Protein 1 Contributes to Hexavalent Chromium-Induced Mitochondrial Respiratory Chain Complex I-Dependent Cytotoxicity

Increased Mitochondrial Fragmentation Mediated by Dynamin-Related Protein 1 Contributes to Hexavalent Chromium-Induced Mitochondrial Respiratory Chain Complex I-Dependent Cytotoxicity

The lipid droplet protein Pgc1 controls the subcellular distribution of phosphatidylglycerol

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

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