SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease

GENIN, E. C.; Bannwarth, S.; Ropert, B.; Mauri-Crouzet, A.; Lespinasse, F.; Auge, G.; Fragaki, K.; Cochaud, C.; Lacas-Gervais, S.; Paquis-Flucklinger, V.

doi:10.1101/2021.05.31.446377

bioRxiv · 10.1101/2021.05.31.446377

SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease

GENIN, E. C.·Bannwarth, S.·Ropert, B.·Mauri-Crouzet, A.·Lespinasse, F.·Auge, G.·Fragaki, K.·Cochaud, C.·Lacas-Gervais, S.·Paquis-Flucklinger, V.

View original source ↗Export metadata ↓

Abstract

CHCHD10 is an ALS/FTD gene, also involved in a large clinical spectrum, that encodes a protein whose precise function within mitochondria is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) to control the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. In affected tissues, SLP2 forms aggregates with prohibitins and the instability of the PHB complex results in activation of OMA1 and accelerated OPA1 proteolysis leading to mitochondrial fragmentation, loss of mitochondrial cristae and apoptosis. Abnormal cristae morphogenesis depends on both the PHB complex destabilization leading to MICOS complex instability, via disruption of OPA1/Mitofilin interaction, and the activation of PINK1-mediated pathways. We also show that the increase of mitophagy found in both heart and hippocampus of Chchd10S59L/+ mito-QC mice is PINK1/Parkin-dependent. Thus, SLP2/PHBs aggregates and destabilization of the PHB complex with PINK1 activation are critical in the sequence of events leading to CHCHD10S59L-related disease.

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

GENIN, E. C., Bannwarth, S., Ropert, B., Mauri-Crouzet, A., Lespinasse, F., Auge, G., Fragaki, K., Cochaud, C., Lacas-Gervais, S., Paquis-Flucklinger, V.. 2021-05-31. SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease. https://doi.org/10.1101/2021.05.31.446377

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗

bioRxiv2021

Ex Vivo Culture Models of Hidradenitis Suppurativa for defining molecular pathogenesis and treatment efficacy of novel drugs

Hidradenitis suppurativa (HS) is a complex inflammatory and debilitating skin disease for which no effective treatment is available. This is partly because of the unavailability of suitable human or animal models with which exact pathobiology of the disease can be defined. Here, we describe the development of air-liquid (A-L) interface, liquid-liquid/liquid-submersion (L-S) and bioreactor (Bio) ex vivo skin culture models. All three ex vivo platforms were effective for culturing skin samples up to day-14, with the tissue architecture and integrity remaining intact for at least 3 days for healthy skin while for 14 days for HS skin. Up to day-3, no significant differences were observed in % early apoptotic cells among all three platforms. However, an increase was observed in late apoptotic/necrotic cells in HS skin at day-3 in A-L and Bio culture of HS skin. These cultures efficiently support the growth of various cells populations, including keratinocytes and immune cells. Profiling of the inflammatory genes using HS skin from these ex vivo cultures showed dynamic expression changes at day-3 and day-14. All of these cultures are necessary to represent the inflammatory gene status of HS skin at day-0 suggesting that not all gene clusters are identically altered in each culture method. Similarly, cytokine/chemokine profiling of the supernatant from vehicle- and drug-treated ex vivo HS cultures again showed better prediction of drug efficacy against HS. Overall, development of these three systems collectively provide a powerful tool to uncover the pathobiology of HS progression and screen various drugs against HS.

pathology↗

bioRxiv2021

Speckle illumination microscopy enables slide-free and non-destructive pathology of human lung adenocarcinoma

Histopathology based on formalin-fixed and paraffin-embedded tissues remains the gold standard for surgical margin assessment (SMA). However, routine pathological practice is lengthy and laborious, failing to provide immediate feedback to surgeons and pathologists for intraoperative decision-making. In this report, we propose a cost-effective and easy-to-use histological imaging method with speckle illumination microscopy (i.e., HiLo). HiLo can achieve rapid and non-destructive imaging of large and fluorescently-labelled resection tissues at an acquisition speed of 5 cm2/min with 1.3-m lateral resolution and 5.8-m axial resolution, demonstrating a great potential as an intraoperative SMA tool that can be used by surgeons and pathologists to detect residual tumors at surgical margins. It is experimentally validated that HiLo enables rapid diagnosis of different subtypes of human lung adenocarcinoma and hepatocellular carcinoma, producing images with remarkably recognizable cellular features comparable to the gold-standard histology. This work will facilitate the clinical translations of HiLo microscopy to improve the current standard-of-care.

pathology↗