The phosphorylation of mitofusin 2 (Mfn2) by the protein kinases PINK1 and/or PKA triggers its degradation by the proteasome and leads to Mfn2 deficiency, a study by researchers in Canada and the UK found.
It is known that low Mfn2 expression leads to impaired mitochondrial fusion, which contributes to unrestricted cell proliferation and apoptosis resistance in diseases such as pulmonary arterial hypertension (PAH) and non-small cell lung cancer. Inhibiting Mfn2 phosphorylation may, therefore, have potential therapeutic benefits in patients with PAH and lung cancer, according to Asish Dasgupta PhD, and the co-authors of the study that was published in The FASEB Journal.
In order to test the hypothesis that the levels of Mfn2 may be reduced due to increased proteasomal degradation triggered by its phosphorylation and to investigate potential protein kinases that may play a role in this process, the team conducted a series of experiments using cell culture.
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They designed a phosphorylation-deficient Mfn2 construct and a constitutively phosphorylated Mfn2 one and compared their effect to that of a wild-type (WT) Mfn2 construct.
They found that WT-Mfn2 increased Mfn2 expression and mitochondrial fusion in both PAH and non-small cell lung cancer cells. This increase in Mfn2 expression resulted in increased apoptosis and decreased cell proliferation. Phosphorylation deficient Mfn2 led to even greater Mfn2 expression and suppressed cell proliferation and induced apoptosis and cell cycle arrest.
Constitutively phosphorylated Mfn2, however, only led to a small increase in Mfn2 expression. But it did not restore mitochondrial fusion. It also did not inhibit cell proliferation or induce apoptosis.
When the researchers silenced PINK1 or PKA expression or blocked the activity of the proteasome, they found that Mfn2 expression was increased. Moreover, mitochondrial fusion was enhanced and apoptosis was induced.
Finally, using a model of non-small cell lung cancer transplantation, the researchers showed that gene therapy with phosphorylation deficient Mfn2 led to greater tumor regression compared to gene therapy with WT-Mfn2.
They concluded that the Mfn2 deficiency seen in conditions such as PAH and non-small cell lung cancer is likely caused by Mfn2-degradation triggered by its phosphorylation by PINK1 and/or PKA.
“Modification of Mfn2 to make it resistant to proteasomal degradation has therapeutic implications for lung cancer and PAH,” they wrote.
Dasgupta A, Chen KH, Lima PDA, et al. PINK1-induced phosphorylation of mitofusin 2 at serine 442 causes its proteasomal degradation and promotes cell proliferation in lung cancer and pulmonary arterial hypertension. FASEB J. 2021;35(8):e21771. doi:10.1096/fj.202100361R