Mitochondria, disease and aging Group, Université Côte d'Azur, Inserm U1081, CNRS UMR7284, IRCAN, CHU de Nice, Nice, France.
Published: October 2022
AI Article Synopsis
Article Abstract
CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing protein 10 interacts with the Stomatin-Like Protein 2 and participates in the stability of the prohibitin complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p.Ser59Leu), we show that Stomatin-Like Protein 2 forms aggregates with prohibitins, found in vivo in the hippocampus and as aggresome-like inclusions in spinal motor neurons of Chchd10S59L/+ mice. Affected cells and tissues display instability of the prohibitin complex, which participates at least in part in the activation of the OMA1 cascade with OPA1 processing leading to mitochondrial fragmentation, abnormal mitochondrial cristae morphogenesis and neuronal death found in spinal cord and the hippocampus of Chchd10S59L/+ animals. Destabilization of the prohibitin complex leads to the instability of the mitochondrial contact site and cristae organizing the system complex, probably by the disruption of OPA1-mitofilin interaction. Thus, Stomatin-Like Protein 2/prohibitin aggregates and destabilization of the prohibitin complex are critical in the sequence of events leading to motor neuron death in CHCHD10S59L-related disease.
Prohibitins (PHBs) are ubiquitously expressed proteins in the mitochondrial inner membrane (MIM) that provide membrane scaffolds for both mitochondrial proteins and phospholipids. Eukaryotic PHB complexes contain two highly homologous PHB subunits, PHB1 and PHB2, which are involved in various cellular processes, including metabolic control through the regulation of mitochondrial dynamics and integrity. Their mechanistic actions at the molecular level, however, particularly those of PHB1, remain poorly understood.
Mitochondrial membrane phospholipid cardiolipin is essential for the stability of several inner mitochondrial membrane protein complexes. We recently showed that the abundance of mitochondrial magnesium channel MRS2 is reduced in models of Barth syndrome, an X-linked genetic disorder caused by a remodeling defect in cardiolipin. However, the mechanism underlying the reduced abundance of MRS2 in cardiolipin-depleted mitochondria remained unknown.
IMol Polish Academy of Sciences, 02-247 Warsaw, Poland; ReMedy International Research Agenda Unit, IMol Polish Academy of Sciences, 02-247 Warsaw, Poland. Electronic address:
- The presequence translocase TIM23 is crucial for transporting mitochondrial proteins into the matrix or inner membrane, with its core components being Tim23 and Tim17, but the details of the human TIM23 complex are not well understood.
- Both TIMM17A and TIMM17B, the human equivalents of Tim17, are regulated by the prohibitin complex, which is necessary for stabilizing these variants.
- The study highlights the role of OCIAD1 in working with prohibitins to protect the TIMM17A variant from degradation, suggesting an important regulatory relationship between OCIAD1, prohibitins, and the TIM23 complex.
Functional divergence of transcription factors (TFs) has driven cellular and organismal complexity throughout evolution, but its mechanistic drivers remain poorly understood. Here we test for new mechanisms using CORONA (CNA) and PHABULOSA (PHB), two functionally diverged paralogs in the CLASS III HOMEODOMAIN LEUCINE ZIPPER (HD-ZIPIII) family of TFs. We show that virtually all genes bound by PHB ( ~ 99%) are also bound by CNA, ruling out occupation of distinct sets of genes as a mechanism of functional divergence.
Millions of people worldwide suffer from musculoskeletal damage, thus using the largest proportion of rehabilitation services. The limited self-regenerative capacity of bone and cartilage tissues necessitates the development of functional biomaterials. Magnetoactive materials are a promising solution due to clinical safety and deep tissue penetration of magnetic fields (MFs) without attenuation and tissue heating.
