MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression

Abstract

Mitochondrial dysfunction is one of the major contributors to neurodegenerative disorders including Parkinson disease. The mitochondrial permeability transition pore is a protein complex located on the mitochondrial membrane. Under cellular stress, the pore opens, increasing the release of proapoptotic proteins, and ultimately resulting in cell death. MicroRNA-7 (miR-7) is a small non-coding RNA that has been found to exhibit a protective role in the cellular models of Parkinson disease. In the present study, miR-7 was predicted to regulate the function of mitochondria, according to gene ontology analysis of proteins that are down-regulated by miR-7. Indeed, miR-7 overexpression inhibited mitochondrial fragmentation, mitochondrial depolarization, cytochrome c release, reactive oxygen species generation, and release of mitochondrial calcium in response to 1-methyl-4-phenylpyridinium (MPP ؉ ) in human neuroblastoma SH-SY5Y cells. In addition, several of these findings were confirmed in mouse primary neurons. Among the mitochondrial proteins identified by gene ontology analysis, the expression of voltage-dependent anion channel 1 (VDAC1), a constituent of the mitochondrial permeability transition pore, was down-regulated by miR-7 through targeting 3-untranslated region of VDAC1 mRNA. Similar to miR-7 overexpression, knockdown of VDAC1 also led to a decrease in intracellular reactive oxygen species generation and subsequent cellular protection against MPP ؉ . Notably, overexpression of VDAC1 without the 3-UTR significantly abolished the protective effects of miR-7 against MPP ؉ -induced cytotoxicity and mitochondrial dysfunction, suggesting that the protective effect of miR-7 is partly exerted through promoting mitochondrial function by targeting VDAC1 expression. These findings point to a novel mechanism by which miR-7 accomplishes neuroprotection by improving mitochondrial health.The mitochondrial permeability transition pore (PTP), 2 which spans both the outer and the inner mitochondrial membranes, is a conductance channel responsible for maintaining the mitochondrial membrane potential. The mitochondrial PTP consists of three proteins: voltage-dependent anion channel 1 (VDAC1), adenine nucleotide transporter (ANT), and cyclophilin D (1). VDAC1 and ANT are integral membrane proteins of the outer and inner mitochondrial membranes, respectively. Together, these two proteins form the conductance channel of the mitochondrial PTP. Cyclophilin D is a mitochondrial matrix protein that associates with ANT and modulates pore function. Under normal physiological conditions, the mitochondrial PTP is maintained in a closed state, allowing mitochondria to remain polarized. Stressful stimuli, such as oxidative stress and accumulation of unfolded proteins, lead to the opening of the mitochondrial PTP (1). As a result, the mitochondrial membrane potential is dissipated, causing depolarization of mitochondria, decrease in ATP production, swelling of mitochondria, efflux of mitochondrial calcium, generation of reactive oxygen spec...

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