ARK5 enhances cell survival associated with mitochondrial morphological dynamics from fusion to fission in human multiple myeloma cells

Abstract

Abstract5′ adenosine monophosphate–activated protein kinase–related kinase 5 (ARK5) is involved in mitochondrial ATP production and associated with poor prognosis of multiple myeloma (MM). However, the molecular mechanisms of ARK5 in MM remain largely unknown. This study examined the pathogenic role of ARK5 in mitochondria by using genetically modified isogenic cell clones with or without ARK5 in human myeloma cell lines, KMS-11 and Sachi, which overexpress ARK5. The biallelic knockout of ARK5 (ARK5-KO) inhibited cell proliferation, colony formation, and migration with increased apoptosis. Mitochondrial fusion was enhanced in ARK5-KO cells, unlike in ARK5 wild-type (ARK5-WT) cells, which exhibited increased mitochondrial fission. Furthermore, ARK5-KO cells demonstrated a lower phosphorylated dynamin–related protein 1 at serine 616, higher protein expression of mitofusin-1 (MFN1) and MFN2, optic atrophy 1 with a lower level of ATP, and higher levels of lactate and reactive oxygen species than ARK5-WT cells. Our findings suggest that ARK5-enhanced myeloma cells can survive associated mitochondrial fission and activity. This study first revealed the relationship between ARK5 and mitochondrial morphological dynamics. Thus, our outcomes show novel aspects of mitochondrial biology of ARK5, which can afford a more advanced treatment approach for unfavorable MM expressing ARK5.

Exploring the Cellular Impact of Size-Segregated Cigarette Aerosols: Insights into Indoor Particulate Matter Toxicity and Potential Therapeutic Interventions

“…To assess mitochondrial superoxide (O 2 – ) production, cells were treated with CAE (OP: 55 μg/mL for SH-SY5Y and 205 μg/mL for HEK293T and A549) for 4 h 37 °C. Then, 100 μL of 1.25 × MitoROS 580 (AAT Bioquest) , was added for an additional 60 min at 37 °C. Fluorescence intensity was measured under the same conditions as above.…”

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

“…The NUAK family of SNF1-like kinase 1 (NUAK1, previously known as AMPK-related protein kinase 5 [ARK5]), together with NUAK2 (previously known as SNF1/AMP kinase-related kinase [SNARK]), form the NUAK subfamily. Most of the current knowledge regarding NUAK1 is derived from the field of oncology, where NUAK1 is known as a tumor survival factor that, amongst other functions, is involved in mitochondrial ATP production and mitochondrial dynamics (i.e., fission and fusion) [ 134 , 135 ]. Notably, in neurons, NUAK1 has very recently been reported to modulate both mitochondrial metabolism and trafficking [ 134 ].…”

“…Notably, in neurons, NUAK1 has very recently been reported to modulate both mitochondrial metabolism and trafficking [ 134 ]. Additionally, this kinase is involved in tumor invasion and metastasis of, for example, colorectal, pancreatic, and gastric cancers [ 135 ]. Interestingly, patients with acute coronary syndrome showed decreased expression of NUAK1 in peripheral blood mononuclear cells (PBMCs) [ 136 ].…”