Targeting the mitochondrial protein YME1L to inhibit osteosarcoma cell growth in vitro and in vivo

Sep 21, 2026

Uploaded by Eliana

Targeting the mitochondrial protein YME1L is evaluated as a strategy to suppress osteosarcoma growth in vitro and in vivo. YME1L mRNA and protein levels are markedly elevated in human osteosarcoma tissues and upregulated in primary and immortalized osteosarcoma cells, with TCGA analysis linking YME1L overexpression to poor survival. Lentiviral shRNA silencing reduces viability, proliferation, migration, triggers cell-cycle arrest and apoptosis, and disrupts mitochondrial function with oxidative injury and DNA damage. YME1L overexpression shows pro-cancer effects, mechanistically involving Akt-S6K and mitochondrial-linked Akt-mTOR signaling, and intratumoral YME1LshRNA AAV inhibits xenograft growth in nude mice.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

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Introduction

Background and clinical need in osteosarcoma

Mitochondria and mitochondrial proteins in tumor growth

YME1L function in mitochondrial inner membrane and AAA family ATPases

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN Targeting the mitochondrial protein YME1L to inhibit osteosarcoma cell growth in vitro and in vivo Xu Sun1,7, Ce Shi2,3,7, Jin Dai 4,7, Mei-Qing Zhang5, Dong-Sheng Pei 2 ✉ and Lei Yang 6 ✉ © The Author(s) 2024 | | | | | --- | --- | --- | | | Exploring novel diagnostic and therapeutic biomarkers is extremely important for osteosarcoma. YME1 Like 1 ATPase (YME1L), locating in the mitochondrial inner membrane, is key in regulating mitochondrial plasticity and metabolic activity. Its expression and potential functions in osteosarcoma are studied in the present study. We show that YME1L mRNA and protein expression is signiﬁcantly elevated in osteosarcoma tissues derived from different human patients. Moreover, its expression is upregulated in various primary and immortalized osteosarcoma cells. The Cancer Genome Atlas database results revealed that YME1Loverexpression was correlated with poor overall survival and poor disease-speciﬁc survival in sarcoma patients. In primary and immortalized osteosarcoma cells, silencing of YME1L through lentiviral shRNA robustly inhibited cell viability, proliferation, and migration. Moreover, cell cycle arrest and apoptosis were detected in YME1L-silenced osteosarcoma cells. YME1L silencing impaired mitochondrial functions in osteosarcoma cells, causing mitochondrial depolarization, oxidative injury, lipid peroxidation and DNA damage as well as mitochondrial respiratory chain complex I activity inhibition and ATP depletion. Contrarily, forced YME1Loverexpression exerted pro-cancerous activity and strengthened primary osteosarcoma cell proliferation and migration. YME1L is important for Akt-S6K activation in osteosarcoma cells. Phosphorylation of Akt and S6K was inhibited after YME1L silencing in primary osteosarcoma cells, but was strengthened with YME1L overexpression. Restoring Akt-mTOR activation by S473Dconstitutively active Akt1 mitigated YME1L shRNA-induced anti-osteosarcoma cell activity. Lastly, intratumoral injection of YME1LshRNA adeno-associated virus inhibited subcutaneous osteosarcoma xenograft growth in nude mice. YME1L depletion, mitochondrial dysfunction, oxidative injury, Akt-S6K inactivation, and apoptosis were detected in YME1L shRNA-treated osteosarcoma xenografts. Together, overexpressed YME1L promotes osteosarcoma cell growth, possibly by maintaining | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | mitochondrial function and Akt-mTOR activation. | | | | | | | | | | | | Cell Death and Disease (2024)15:346; [https://doi.org/10.1038/s41419-024-06722-6](https://doi.org/10.1038/s41419-024-06722-6) | | | | | | INTRODUCTION Osteosarcoma (OS) is a common malignancy in the bone among children and teenagers [1, 2] . The current clinical treatments, including chemotherapy (doxorubicin, cisplatin and methotrexate etc), molecularly-targeted therapy, radiotherapy and tumorresection surgery [3–5], have been able to signiﬁcantly improve the prognosis of patients with OS [6] . However, for the patients with the recurrent, metastatic, and other advanced tumors, the 5 year overall survival is still low (close to 20%) [2, 7] . It is therefore urgent to explore novel molecular targets vital for the oncogenesis and tumorigenesis of OS [8–10] . Mitochondria are the main organelle for energy metabolism, ATP synthesis and macromolecules biosynthesis [11, 12] . Elevated mitochondrial bioenergetics is required for the growth of OS cells and the progression of the tumor [13–15] . A number of key mitochondrial proteins are required for maintaining mitochondrial functions and the hyper-proliferative activity of OS cells. For example, Zhuo et al. recently reported that the mitochondrial protein ADCK1 (AarF domain-containing kinase 1) is overexpressed in OS and is requir

FAQs

How is YME1L involved in osteosarcoma according to the study?

YME1L mRNA and protein expression are significantly elevated in osteosarcoma tissues and upregulated in osteosarcoma cells. TCGA results associate YME1L overexpression with poorer overall and disease-specific survival.

What is the effect of silencing YME1L on osteosarcoma cells?

Lentiviral shRNA-mediated YME1L silencing robustly inhibits cell viability, proliferation, and migration. It also induces cell-cycle arrest and apoptosis and impairs mitochondrial function, including depolarization, oxidative injury, lipid peroxidation, and DNA damage.

How does YME1L influence signaling and tumor growth in vivo?

YME1L supports Akt-S6K activation; silencing inhibits phosphorylation of Akt and S6K, while overexpression strengthens it. Restoring Akt-mTOR activation with a constitutively active Akt1 reduces the anti-osteosarcoma effect of YME1L knockdown, and intratumoral YME1LshRNA AAV suppresses xenograft growth in nude mice.

Sep 21, 2026

Uploaded by Eliana