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<p>In breast cancer, the inner mitochondrial membrane fusion protein Optic Atrophy 1 (OPA1) is upregulated and its inhibition reverses acquired chemoresistance. However, it remains unclear whether OPA1 inhibition also targets normal breast cells. We show that OPA1 upregulation is a hallmark of metastatic breast cancer cells, which are selectively susceptible to OPA1 inhibition compared to isogenic normal or localized tumor cells. In an isogenic model spanning normal, transformed, and metastatic breast cancer cells, levels of Mitofusin 1 (MFN1) progressively declined while dynamin related protein 1 (DRP1) became increasingly active, correlating with fragmented mitochondria during cancer progression. Meanwhile, OPA1 levels were elevated in invasive cells characterized by mitochondrial fragmentation, tight cristae, and high respiration. OPA1 deletion selectively reduced metastatic cells mitochondrial respiration, proliferation, and migration. Specific OPA1 inhibitors MYLS22 and Opitor-0 diminished migration and increased death of metastatic cells, underscoring OPA1 as a selective vulnerability of metastatic breast cancer.</p>

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Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月21日

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  • Antigoni Diokmetzidou,
  • Aurora Maracani,
  • Anna Pellattiero,
  • Mauricio Cardenas-Rodriguez,
  • Erwan A. Rivière,
  • Luca Scorrano

摘要

In breast cancer, the inner mitochondrial membrane fusion protein Optic Atrophy 1 (OPA1) is upregulated and its inhibition reverses acquired chemoresistance. However, it remains unclear whether OPA1 inhibition also targets normal breast cells. We show that OPA1 upregulation is a hallmark of metastatic breast cancer cells, which are selectively susceptible to OPA1 inhibition compared to isogenic normal or localized tumor cells. In an isogenic model spanning normal, transformed, and metastatic breast cancer cells, levels of Mitofusin 1 (MFN1) progressively declined while dynamin related protein 1 (DRP1) became increasingly active, correlating with fragmented mitochondria during cancer progression. Meanwhile, OPA1 levels were elevated in invasive cells characterized by mitochondrial fragmentation, tight cristae, and high respiration. OPA1 deletion selectively reduced metastatic cells mitochondrial respiration, proliferation, and migration. Specific OPA1 inhibitors MYLS22 and Opitor-0 diminished migration and increased death of metastatic cells, underscoring OPA1 as a selective vulnerability of metastatic breast cancer.