Key Takeaways & Executive Findings
- •• ATIP is downregulated in prostate cancer tissues and negatively correlates with patient disease-free survival, suggesting its role as a tumor suppressor. • Silencing ATIP promotes mitochondrial fission and enhances prostate cancer cell migration and invasion, linking mitochondrial dynamics to metastasis. • Reconstitution of ATIP1 in ATIP-deficient cells attenuates mitochondrial trafficking and tumor cell movement, confirming its inhibitory function. • ATIP1 emerges as a potential prognostic biomarker and therapeutic target for prostate cancer metastasis.
Abstract
Mitochondria play a fundamental role in cell survival and motility. Abnormalities in mitochondria are associated with carcinogenesis, especially with tumor metastasis. In this study, we explore the biological function of ATIP1, which is a mitochondrial-located isoform of angiotensin II AT2 receptor interacting proteins (ATIPs) in prostate cancer cells. The results showed that ATIP is downregulated in prostate cancer tissues and is negatively correlated with the disease-free survival rate of prostate cancer patients. Silencing of ATIP promotes mitochondrial fission and enhances tumor cell migration and invasion. Reconstitution of ATIP1 in ATIP-deficient cells significantly attenuates mitochondrial trafficking and tumor cell movement. Therefore, ATIP1 is a negative regulator of mitochondrial dynamics and tumor cell motility and is also a potential biomarker for predicting prostate cancer malignancy.
1. Introduction
A hallmark of cancer is tissue invasion and metastasis [1]. Mitochondria exist as a dynamic network and are critical for multiple cellular functions, including cell growth, cell death and cell metastasis [2‒5]. Morphologically, mitochondria are characterized by highly dynamic structures of long interconnected tubules with short isolated dots, which are controlled by a series of large GTPase proteins through interchange of fission and fusion events [6]. Mitochondrial fusion is controlled by Mitofusin 1/2 (Mfn1/2) [7] and optic atrophy 1 (OPA1) [8], and fission is modulated by dynamin-related protein 1 (Drp1) [9], fission protein 1 (Fis1) [10] and mitochondrial fission factor (Mff) [11]. Dysfunction of these large GTPase proteins could result in abnormalities in mitochondrial shape/size and subcellular position, which in turn can lead to an incomplete energy supply in response to stimulation from the extracellular environment [6,12].
Accumulating evidence suggests that an imbalance in mitochondrial fission and fusion is strongly associated with tumorigenesis [13], including metabolic reprogramming [14], immune escape [15] and biogenesis [16]. Compared with normal tissues, mitochondrial fragmentation occurs more frequently in multiple cancer cell types, including breast cancer [17], pancreatic cancer [18], melanoma [19] and neuroblastoma [20]. In addition, various mitochondrial proteins are involved in the regulation of tumor cell movement through the activation of mitochondrial fission. For instance, wild-type mitochondrial isocitrate dehydrogenase 2 (IDH2) promotes prostate cancer metastasis by excessively activating mitochondrial division, whereas inhibition of the mitochondrial fission process can rescue the invasion associated with IDH2 knockdown [21]. Disrupting the ubiquitination of the mitochondrial protein SNPH increases the recruitment of Drp1 to mitochondria and promotes tumor cell motility [22].
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Haokun Yuan, Ruiqin Fang, Chi Fu, Shuo Wang, Xiaoqin Tong, Deyi Feng, Xiaoqing Wei, Xirong Hu, Yuan Wang (2026). ATIP/ATIP1 regulates prostate cancer metastasis through mitochondrial dynamic-dependent signaling. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024006
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Frequently Asked Questions
What is the role of ATIP1 in prostate cancer?
ATIP1 is a mitochondrial-located tumor suppressor that negatively regulates mitochondrial dynamics and tumor cell motility. Its downregulation in prostate cancer is associated with poor prognosis and increased metastasis.
How does ATIP1 affect mitochondrial dynamics?
ATIP1 inhibits mitochondrial fission. Silencing ATIP promotes mitochondrial fragmentation, while reconstitution of ATIP1 attenuates mitochondrial trafficking and fission, thereby reducing cell migration and invasion.
What is the clinical significance of ATIP1 expression?
ATIP1 expression is negatively correlated with disease-free survival in prostate cancer patients, making it a potential prognostic biomarker and therapeutic target for preventing metastasis.
Which proteins are involved in mitochondrial fission and fusion?
Mitochondrial fusion is controlled by Mfn1/2 and OPA1, while fission is modulated by Drp1, Fis1, and Mff. Imbalance in these processes is linked to tumorigenesis.
What is the relationship between mitochondrial dynamics and cancer metastasis?
Excessive mitochondrial fission promotes tumor cell migration and invasion. Proteins like IDH2 and SNPH can enhance fission and metastasis, while ATIP1 acts as a negative regulator.
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