Lipid signalling drives proteolytic rewiring of mitochondria by YME1L

MacVicar, Thomas; Ohba, Yohsuke; Nolte, Hendrik; Mayer, Fiona Carola; Tatsuta, Takashi; Sprenger, Hans‐Georg; Lindner, Barbara; Zhao, Yue; Li, Jiahui; Bruns, Christiane; Krüger, Marcus; Habich, Markus; Riemer, Jan; Schwarzer, Robin; Pasparakis, Manolis; Henschke, Sinika; Brüning, Jens C.; Zamboni, Nicola; Langer, Thomas

doi:10.1038/s41586-019-1738-6

Cited by 134 publications

(143 citation statements)

References 51 publications

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“…It is also suggested that PE homeostasis is relevant for fusion, as both S-Mgm1 protein and mitochondrial fusion are decreased when mitochondrial PE levels are low (Chan and McQuibban, 2012;Joshi et al, 2012). Recently, a lipid signaling cascade dependent on the PA phosphatase LIPIN1 was found to modulate mitochondrial PE abundance (MacVicar et al, 2019). mTORC1 inhibition by hypoxia or amino acid starvation leads to LIPIN1 activation, decreasing PA amounts and ultimately mitochondrial PE levels, which then promotes proteolysis by YME1L (MacVicar et al, 2019;Peterson et al, 2011).…”

Section: Mitochondrial Fusionmentioning

confidence: 99%

Phospholipid ebb and flow makes mitochondria go

Acoba

Senoo

Claypool

2020

Journal of Cell Biology

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Mitochondria, so much more than just being energy factories, also have the capacity to synthesize macromolecules including phospholipids, particularly cardiolipin (CL) and phosphatidylethanolamine (PE). Phospholipids are vital constituents of mitochondrial membranes, impacting the plethora of functions performed by this organelle. Hence, the orchestrated movement of phospholipids to and from the mitochondrion is essential for cellular integrity. In this review, we capture recent advances in the field of mitochondrial phospholipid biosynthesis and trafficking, highlighting the significance of interorganellar communication, intramitochondrial contact sites, and lipid transfer proteins in maintaining membrane homeostasis. We then discuss the physiological functions of CL and PE, specifically how they associate with protein complexes in mitochondrial membranes to support bioenergetics and maintain mitochondrial architecture.

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Section: Mitochondrial Fusionmentioning

confidence: 99%

Phospholipid ebb and flow makes mitochondria go

Acoba

Senoo

Claypool

2020

Journal of Cell Biology

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“…1 ). However, stresses such as hypoxia or nutrient deprivation induce a lipid signaling cascade upon inactivation of mechanistic target of rapamycin complex 1 (mTORC1) to reduce PE levels at the IMM, leading to activation of YME1L-mediated proteolysis of mitochondrial proteins and subsequent inhibition of mitochondrial biogenesis ( MacVicar et al, 2019 ). This involves activation of LIPIN1, a substrate of mTORC1 that is phosphorylated and hence inhibited under basal conditions (e.g., available oxygen and nutrients).…”

Section: Mitochondrial Lipid Signalingmentioning

confidence: 99%

Mitochondria as intracellular signaling platforms in health and disease

Tan

Finkel

2020

Journal of Cell Biology

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Mitochondria, long viewed solely in the context of bioenergetics, are increasingly emerging as critical hubs for intracellular signaling. Due to their bacterial origin, mitochondria possess their own genome and carry unique lipid components that endow these organelles with specialized properties to help orchestrate multiple signaling cascades. Mitochondrial signaling modulates diverse pathways ranging from metabolism to redox homeostasis to cell fate determination. Here, we review recent progress in our understanding of how mitochondria serve as intracellular signaling platforms with a particular emphasis on lipid-mediated signaling, innate immune activation, and retrograde signaling. We further discuss how these signaling properties might potentially be exploited to develop new therapeutic strategies for a range of age-related conditions.

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“…Regulation of mitochondrial dynamics due to processing of the dynamin-like GTPase OPA1 is perhaps one of the best characterised roles of YME1L (76,106). Changes to OPA1 processing has been implicated in altering mitochondrial morphology in response to different cellular stresses, metabolic and environmental demands (105,107,108). Whilst mitochondrial morphology has been reported to be modified during infection with Listeria monocytogenes, Vibrio cholerae and L. pneumophila, thus far, no study has demonstrated any mitochondrial network alterations during C. burnetii infection (35,(109)(110)(111).…”

Section: Discussionmentioning

confidence: 99%

Proteomic identification ofCoxiella burnetiieffector proteins targeted to the host cell mitochondria during infection

Fielden

Scott

Palmer

et al. 2020

Preprint

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Modulation of the host cell is integral to the survival and replication of microbial pathogens. Several intracellular bacterial pathogens deliver a cohort of bacterial proteins, termed ‘effector proteins’ into the host cell during infection by sophisticated protein translocation systems which manipulate cellular processes and functions. Despite the importance of these proteins during infection the functional contribution of individual effectors is poorly characterised, particularly in intracellular bacterial pathogens with large effector protein repertoires. Technical caveats have limited the capacity to study these proteins during a native infection, with many effector proteins having only been demonstrated to be translocated during over-expression of tagged versions. Here we present development of a novel strategy to examine effector proteins in the context of infection. We coupled a broad, unbiased proteomics-based screen with organelle purification to study the host-pathogen interactions occurring between the host cell mitochondrion and the Gram-negative, Q fever pathogen Coxiella burnetii. We identify 4 novel mitochondrially-targeted C. burnetii effector proteins, renamed Mitochondrial Coxiella effector protein (Mce) B to E. Examination of the subcellular localisation of ectopically expressed proteins in epithelial cells confirmed the mitochondrial localisation, demonstrating the robustness of our approach. Subsequent biochemical analysis and affinity enrichment proteomics of one of these effector proteins, MceC, revealed the protein is imported into mitochondria and can interact with components of the mitochondrial quality control machinery. Our study adapts high-sensitivity proteomics to the study of intracellular host-pathogen interactions occurring during infection, providing a robust strategy to examine the sub-cellular localisation of effector proteins during native infection. This approach could be applied to a range of pathogens and host cell compartments to provide a rich map of effector dynamics throughout infection.

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Lipid signalling drives proteolytic rewiring of mitochondria by YME1L

Cited by 134 publications

References 51 publications

Phospholipid ebb and flow makes mitochondria go

Phospholipid ebb and flow makes mitochondria go

Mitochondria as intracellular signaling platforms in health and disease

Proteomic identification ofCoxiella burnetiieffector proteins targeted to the host cell mitochondria during infection

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