Mitochondria-Dependent Local Caspase Activation and Mitofusin 2-Mediated Mitophagy in Neurodegeneration



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Mitochondria are critical regulators of neuronal physiology. They play a pivotal role in energy supply and Ca2+ buffering. Thus, mitochondria can sustain the synapse and neuronal function. In this regard, the mitochondria with an impaired capacity of bioenergetics or Ca2+ buffering will lead to synapse failure and neurodegeneration. Moreover, emerging evidence has shown that damaged mitochondria are also involved in local caspase activation, which coincides with spine pruning and neurodegeneration. However, the impacts of local caspase signaling on spine dynamics and neurodegeneration are still not clarified. To clarify them is critical for neurological disorders, in which the mitochondrial deficits are prominent and hard to be fixed. Additionally, as a pivotal mitochondrial enzyme – the F1Fo ATP synthase, dysfunction of it will lead to diseases with spinopathy. To this end, we inhibited the F1Fo ATP synthase by applying the sublethal oligomycin A to primary cultured neurons. Then, it induced the mitochondrial dysfunction and local caspase signaling. Following this, we blocked the caspase signaling through its inhibitor to determine whether it can rescue the spine elimination. In this case, we can dissect the caspase signaling out of mitochondrial energy supply and examine how much the caspase signaling attributes to spine pruning. Furthermore, we will find new ways to prevent the senescence of neurons through caspase inhibition. Moreover, mitochondrial quality control is of paramount importance for neuronal survival. Notably, mitophagy is a vital mechanism for maintenance of mitochondrial quality control. A previous study has shown that Mitofusin2 (Mfn2) plays a key role in mediating mitophagy in cardiomyocytes, which was demonstrated by decreased mitophagy in Mfn2 knockdown cardiomyocytes. In addition, lowered expression levels of Mfn2 have been repeatedly found in many neurodegenerative diseases like Alzheimer’s disease, which is characterized by the accumulation of damaged mitochondrial and mitophagosomes in neurons. In this regard, reduced Mfn2 expression may lead to compromised mitophagy and mitochondrial quality control. However, whether Mfn2 is indispensable for facilitating mitophagy has not been fully investigated. To this end, we knocked down Mfn2 in primary cultured neurons. Then, we examined the state of mitophagy. Intriguingly, we observed more mitophagosomes formation in Mfn2 knock-down neurons. It indicates the Mfn2 is not necessary for mitophagy induction. Such discrepancy may arise from the heterogeneity of different cell types. Also, it may arise from some alternative adaptor proteins, which can activate mitophagy. From previous reports, people pulled down the conjugated proteins from the outer mitochondrial membrane (OMM) of senescent and healthy neurons. After screening them by mass spectrum, they found that several OMM proteins may be the potential receptors for mitophagosome formation. Among them, Voltage-Dependent Anion Channel (VDAC) is the one most reported for mitophagy induction. Accordingly, we will further knockdown VDAC in Mfn2 knock-down neurons and examine the mitophagy states. In this case, we can determine whether VDAC can work as an Mfn2-independent alternative trigger for mitophagy in neurons. In all, both local caspases signaling and mitophagy play essential roles in neurodegeneration. Regulation of them may provide us new avenues for treating neurodegenerative diseases.



Spine -- Abnormalities, Bone remodeling, Guanosine triphosphatase, Neuroplasticity, Mitochondria