Mitochondrial dynamic alterations regulate melanoma cell progression

Abstract

Research on mitochondrial fusion and fission (mitochondrial dynamics) has gained much attention in recent years, as it is important for understanding many biological processes, including the maintenance of mitochondrial functions, apoptosis, and cancer. The rate of mitochondrial biosynthesis and degradation can affect various aspects of tumor progression. However, the role of mitochondrial dynamics in melanoma progression remains controversial and requires a mechanistic understanding to target the altered metabolism of cancer cells. Therefore, in our study, we disrupted mitochondrial fission with mdivi-1, the reported inhibitor of dynamin related protein 1 (Drp1), and knocked down Drp1 and Mfn2 to evaluate the effects of mitochondrial dynamic alterations on melanoma cell progression. Our confocal study results showed that mitochondrial fission was inhibited both in mdivi-1 and in Drp1 knockdown cells and, in parallel, mitochondrial fusion was induced. We also found that mitochondrial fission inhibition by mdivi-1 induced cell death in melanoma cells. However, silencing Drp1 and Mfn2 did not affect cell viability, but enhanced melanoma cell migration. We further show that dysregulated mitochondrial fusion by Mfn2 knockdowns suppressed the oxygen consumption rate of melanoma cells. Together, our findings suggest that mitochondrial dynamic alterations regulate melanoma cell migration and progression.

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

“…4,19 Mdivi-1 increased OCR in non-cancer cells like mouse neuroblastoma 58 but deceased OCR in human ductus arteriosus smooth muscle cells. 59 Similar to these findings, studies showed that mdivi-1 increased OCR in some cancer cells 60,61 but decreased OCR in other cancer cells. 25,62 To better understand the regulatory role of DRP1 in cancer metabolism, we used [U- 13 C] glucose tracing to directly reveal the intracellular glucose metabolism in DRP1-deficient H460 lung cancer cells and in multiple mdivi-1-treated cancer cell lines.…”

Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer

“…It is worth noting that the higher expression of Mfn2 has also been reported in lung adenocarcinoma tissues as compared to adjacent normal tissues, and Mfn2 knockdown results in impaired cancer cell proliferation (81). In ovarian cancer (82), breast cancer (83), and melanoma (84), Mfn2 knockdown suppresses oxygen consumption rate (OCR). In pancreatic cancer cells (PANC-1), Mfn2 knockdown enhances mitochondria-dependent energy metabolism by promoting activity of electron transport chain complexes (85).…”

Piscidin-1 Induces Apoptosis via Mitochondrial Reactive Oxygen Species-Regulated Mitochondrial Dysfunction in Human Osteosarcoma Cells

“…Mitochondrial fission and fusion are essential processes that require many specific proteins, including the mechanical enzymes, which physically alter the mitochondrial membrane, and adapter proteins, which modulate the interaction of these mechanical proteins with organelles. The fusion proteins, including mitofusins (MFN1, MFN2) and optic atrophy (OPA1), as well as fission proteins, including mitochondrial fission 1 (FIS1) and dynamin-1-like (DRP1), play an important role in the dynamic changes of the mitochondria 19 , and although incompletely understood, mitochondrial morphological changes appear to be involved in several activities critical to cell health and tumor cells 20 . Based on cellular process involvement, mitochondrial dynamic imbalance may be responsible for the mitochondrial dysfunction of many diseases.…”