{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMitochondrial function and integrity are maintained by a series of tightly regulated proteolytic events in which specific protein complexes, such as the m‐AAA proteases, play a central role. These proteases—composed of subunits including paraplegin, AFG3L1, and AFG3L2—mediate the processing of dynamin‐related GTPases like OPA1, thereby modulating mitochondrial morphology and bioenergetics. Differential subunit composition of these complexes confers distinct substrate specificities and proteolytic efficiencies, an observation underscoring the evolutionary divergence in mitochondrial protein quality control mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysfunction in these mitochondrial proteolytic systems is intimately linked to neurodegenerative phenotypes. In particular, defective mitochondrial processing is associated with axonal degeneration observed in disorders such as hereditary spastic paraplegia. Aberrant activity leads to impaired respiratory complex stability, mitochondrial DNA loss, and eventual neuronal demise, while additional players such as the NAD+‐consuming enzyme SARM1 further modulate the pace and extent of neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementing these mitochondrial-centered mechanisms, recent studies have begun to illuminate the function of a short, evolutionarily conserved secreted micropeptide—NICOL1 (also referred to as C4ORF48 or Cf48). NICOL1 is expressed abundantly in the brain during cortical and cerebellar development, suggesting a role as a novel neuropeptide that may contribute to fine-tuning neuronal development and function. In parallel, NICOL1 expression in peripheral tissues and its ability to interact with mRNAs of pro-fibrotic genes implicate it in the promotion of renal fibrosis, offering insights into its broader contribution to both neurodevelopmental disorders and chronic kidney disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stéphane Duvezin-Caubet, Mirko Koppen, Johannes Wagener, et al. "}, {"type": "b", "children": [{"type": "t", "text": "OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-02-0164"}], "href": "https://doi.org/10.1091/mbc.e07-02-0164"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17615298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17615298"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Paola Martinelli, Veronica La Mattina, Andrea Bernacchia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddp124"}], "href": "https://doi.org/10.1093/hmg/ddp124"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19289403"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19289403"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mirko Koppen, Florian Bonn, Sarah Ehses, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autocatalytic processing of m-AAA protease subunits in mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e09-03-0218"}], "href": "https://doi.org/10.1091/mbc.e09-03-0218"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19656850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19656850"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Giuseppe Mancuso, Esther Barth, Pietro Crivello, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alternative splicing of Spg7, a gene involved in hereditary spastic paraplegia, encodes a variant of paraplegin targeted to the endoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0036337"}], "href": "https://doi.org/10.1371/journal.pone.0036337"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22563492"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22563492"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Irene Sambri, Filomena Massa, Francesca Gullo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EBioMedicine (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ebiom.2020.103050"}], "href": "https://doi.org/10.1016/j.ebiom.2020.103050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33045469"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33045469"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Carolina Montoro-Gámez, Hendrik Nolte, Thibaut Molinié, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awad136"}], "href": "https://doi.org/10.1093/brain/awad136"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37086482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37086482"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sabine Endele, Claudia Nelkenbrecher, Annegret Bördlein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "C4ORF48, a gene from the Wolf-Hirschhorn syndrome critical region, encodes a putative neuropeptide and is expressed during neocortex and cerebellar development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogenetics (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10048-011-0275-8"}], "href": "https://doi.org/10.1007/s10048-011-0275-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21287218"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21287218"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jiayi Yang, Hongjie Zhuang, Jinhua Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI178392"}], "href": "https://doi.org/10.1172/JCI178392"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38625739"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38625739"}]}]}]}