Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination

Sen, Ayesha; Boix, Julia; Pla‐Martín, David

doi:10.1080/15548627.2023.2170959

Cited by 6 publications

(2 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Damage to mtDNA induces mitochondrial membrane remodeling and recruitment of endosomes to mitochondrial nucleoids. Non-cononic, endosome-dependent mitophagy promotes the removal of mtDNA fragments and is associated with the ATAD3 (mitochondrial ATPase)-SAMM50 axis (which controls mitochondrial cristae architecture), in which SAMM50 regulates BAK clustering and nucleoid release and facilitates their transfer to endosomes which mature with the participation of the VPS35 protein ( Sen et al, 2022 ; Sen et al, 2023 ). SAMM50 interacts with VPS35 in the outer mitochondrial membrane and sequesters and eliminates mtDNA, which prevents the development of an enhanced immune response ( Sen et al, 2022 ).…”

Section: Functions Of Prohibitins In Relation To Their Localization I...mentioning

confidence: 99%

Prohibitions in the meta-inflammatory response: a review

Todosenko,

Yurova,

Vulf

et al. 2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

Prohibitins are the central regulatory element of cellular homeostasis, especially by modulating the response at different levels: Nucleus, mitochondria and membranes. Their localization and interaction with various proteins, homons, transcription and nuclear factors, and mtDNA indicate the globality and complexity of their pleiotropic properties, which remain to be investigated. A more detailed deciphering of cellular metabolism in relation to prohibitins under normal conditions and in various metabolic diseases will allow us to understand the precise role of prohibitins in the signaling cascades of PI3K/Akt, Raf/MAP/ERK, STAT3, p53, and others and to fathom their mutual influence. A valuable research perspective is to investigate the role of prohibitins in the molecular and cellular interactions between the two major players in the pathogenesis of obesity—adipocytes and macrophages - that form the basis of the meta-inflammatory response. Investigating the subtle intercellular communication and molecular cascades triggered in these cells will allow us to propose new therapeutic strategies to eliminate persistent inflammation, taking into account novel molecular genetic approaches to activate/inactivate prohibitins.

show abstract

Section: Functions Of Prohibitins In Relation To Their Localization I...mentioning

confidence: 99%

Prohibitions in the meta-inflammatory response: a review

Todosenko,

Yurova,

Vulf

et al. 2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…Another interesting question involves how MFN2 loss of function drives mtDNA release to stimulate both TLR9 and cGAS-STING inflammation. In this regard, several recent studies are relevant to endosomal-mediated mtDNA release (53)(54)(55). A model seems to be emerging where, in the context of stalled mtDNA replication intermediates, enlarged nucleoid clusters are transferred directly into early endosomes, where the mtDNA can be detected by TLR9.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

The MFN2 Q367H variant from a patient with late-onset distal myopathy reveals a novel pathomechanism connected to mtDNA-mediated inflammation

Zaman,

Sharma,

Almutawa

et al. 2024

Preprint

View full text Add to dashboard Cite

BackgroundMFN2encodes a multifunctional mitochondrial protein best known for its role mitochondrial fusion. While pathogenic variants inMFN2typically cause Charcot-Marie-Tooth disease subtype 2A, an axonal peripheral neuropathy, exome sequencing identified an uncharacterizedMFN2variant, Q367H, in a patient diagnosed with late-onset distal myopathy without peripheral neuropathy. Although impaired mitochondrial fusion can cause mtDNA-mediated inflammation via TLR9 activation of NF-kB, which is linked to myopathy in a mouse model of MFN1 deficiency, this pathway has not yet been functionally linked toMFN2pathology.MethodsTo investigate if the Q367H MFN2 variant contributes to the patient phenotype, we applied several biochemical and molecular biology techniques to characterize patient fibroblasts and transdifferentiated myoblasts for several functions mediated by MFN2. We also examined TLR9 and cGAS-STING mtDNA-mediated inflammatory pathways.FindingsPatient fibroblasts showed changes consistent with impairment of several MFN2 functions. When grown in standard glucose media, patient fibroblasts had reduced oxidative phosphorylation and elevated levels of lipid droplets. When grown in galactose media, patient fibroblasts had fragmented mitochondria, reduced mito-ER contact sites, and enlarged mtDNA nucleoids. Notably, under both media conditions, mtDNA was present outside of the mitochondrial network, where it co-localized with early endosomes. We also observed activation of both TLR9/NF-kB and cGAS-STING inflammation in fibroblasts. Moreover, the inflammatory signaling was increased 3-10 fold in transdifferentiated patient myoblasts, which also exhibited reduced mito-ER contacts and altered mtDNA nucleoids.InterpretationWe report a patient with myopathy, but without the typical peripheral neuropathy associated withMFN2disease variants. As elevated inflammation can cause myopathy, linking the Q367H MFN2 variant with elevated TLR9 and cGAS/STING signaling, which is amplified in transdifferentiated myoblasts, provides novel insight into the patient’s phenotype. Thus, we establish a potential novel pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.

show abstract

Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2

Zhou,

Kang,

et al. 2024

Cellular Signalling

View full text Add to dashboard Cite

Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination

Cited by 6 publications

References 1 publication

Prohibitions in the meta-inflammatory response: a review

Prohibitions in the meta-inflammatory response: a review

The MFN2 Q367H variant from a patient with late-onset distal myopathy reveals a novel pathomechanism connected to mtDNA-mediated inflammation

Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2

Contact Info

Product

Resources

About