Mitochondrial micropeptide MOXI promotes fibrotic gene transcription by translocation to the nucleus and bridging N-acetyltransferase 14 with transcription factor c-Jun

Li, Jinhua; Qu, Xinli; Guan, Chengnong; Luo, Ning; Chen, Huiting; Li, Andy; Zhuang, Hongkai; Yang, Jing; Diao, Hongyan; Zeng, Shuhan; Wang, Qing; Fan, Jinjin; Jiang, Mengjie; Bai, Xiaoyan; Ye, Zhiming; Jiang, Xiaoyun; Chen, Wei; Yu, Xueqing

doi:10.1016/j.kint.2023.01.024

Cited by 9 publications

(11 citation statements)

References 50 publications

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“…In addition, MDPs also improve obesity and diabetes by regulating cellular metabolism. Short open-reading frames (sORF) in mitochondrial DNA has recently been found to encode micropeptides (peptides of no more than 100 amino acids) [5]. Three MDPs encoded by sORF have been identified, including humanin, small humanin-like peptides (SHLP), and MOTS-c.…”

Section: Introductionmentioning

confidence: 99%

The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism

Zhang,

Huang,

Zhang

et al. 2024

Antioxidants

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Radiation pneumonitis (RP) is a prevalent and fatal complication of thoracic radiotherapy due to the lack of effective treatment options. RP primarily arises from mitochondrial injury in lung epithelial cells. The mitochondrial-derived peptide MOTS-c has demonstrated protective effects against various diseases by mitigating mitochondrial injury. C57BL/6 mice were exposed to 20 Gy of lung irradiation (IR) and received daily intraperitoneal injections of MOTS-c for 2 weeks. MOTS-c significantly ameliorated lung tissue damage, inflammation, and oxidative stress caused by radiation. Meanwhile, MOTS-c reversed the apoptosis and mitochondrial damage of alveolar epithelial cells in RP mice. Furthermore, MOTS-c significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells and primary mouse lung epithelial cells. Mechanistically, MOTS-c increased the nuclear factor erythroid 2-related factor (Nrf2) level and promoted its nuclear translocation. Notably, Nrf2 deficiency abolished the protective function of MOTS-c in mice with RP. In conclusion, MOTS-c alleviates RP by protecting mitochondrial function through an Nrf2-dependent mechanism, indicating that MOTS-c may be a novel potential protective agent against RP.

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Section: Introductionmentioning

confidence: 99%

The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism

Zhang,

Huang,

Zhang

et al. 2024

Antioxidants

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“…In line with this, loss of Mtln impacts mitochondrial respiration and ROS production 1,[8][9][10][11] . In addition, several studies support that Mtln affects various other pathways and phenotypes, including lipid metabolism 2,8,[12][13][14] , mitochondrial-ER contacts and ER stress signaling 10 , cancer cell migration/invasion 15 , skeletal muscle performance 2,9,13 , myocyte differentiation or regeneration 9,16 , and normal 17 and diseased kidney 18 phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…Most recently, carnitine palmitoyl transferase 1b (Cpt1b) was co-immunoprecipitated with endogenous Mtln 14 . Additionally, biomolecular fluorescence complementation screening in HTC75 fibrosarcoma cells and HEK293T cells identified cI subunit Ndufa7 15 and N-acetyltransferase 14 (Nat14) 18 , respectively, as top hits. Despite these findings, a consensus molecular function for Mtln remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury

Stein,

Zhang,

Witmer

et al. 2024

Preprint

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SUMMARYWe and others discovered a highly-conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress. We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally-relevant role for Mtln in cardioprotection. Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.

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“…9 Micropeptides have to date been found involved in multiple organisms performing diverse functions, including neuroinflammation regulation, 10 viral multiplication, 11 and gene transcription. 12 Micropeptides are mostly enriched in the translation region of ncRNAs and perform specific roles. 13,14 Proteins including micropeptide with diverse structures and biological activities constitute the complexity of cells and organisms.…”

Section: Introductionmentioning

confidence: 99%

“…The sORFs are a class of noncanonical ORFs with sequence length <300 nucleotides and exist in noncoding RNAs as well as in ribosomal RNAs and antisense transcripts 9 . Micropeptides have to date been found involved in multiple organisms performing diverse functions, including neuroinflammation regulation, 10 viral multiplication, 11 and gene transcription 12 . Micropeptides are mostly enriched in the translation region of ncRNAs and perform specific roles 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Subcellular localization and relevant mechanisms of human cancer‐related micropeptides

Deng,

Xu,

Jie

et al. 2023

The FASEB Journal

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Rapid advances in high‐quality sequencing and bioinformatics have invalidated the argument that noncoding RNAs (ncRNAs) are junk transcripts that do not encode proteins. Increasing evidence suggests that small open reading frames (sORFs) in ncRNAs can encode micropeptides and polypeptides within 100 amino acids in length. Several micropeptides have been characterized and proven to have various functions in human physiology and pathology, particularly in cancer. The present review mainly highlights the latest studies on ncRNA‐encoded micropeptides in different cancers and categorizes them based on their subcellular localization, thereby providing a theoretical basis for micropeptide applications in the early diagnosis and prognosis of cancer and as therapeutic targets. However, considering the inherent characteristics of micropeptides and the limitations of the assay technology methods, more detailed information is warranted.

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Mitochondrial micropeptide MOXI promotes fibrotic gene transcription by translocation to the nucleus and bridging N-acetyltransferase 14 with transcription factor c-Jun

Cited by 9 publications

References 50 publications

The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism

The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury

Subcellular localization and relevant mechanisms of human cancer‐related micropeptides

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