Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease

Abstract

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-␤-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

“…Intracellular mitochondria distribution is of vital importance to neurons. The morphological complexity and dependence on mitochondria as the energy supply at numerous selective sites of neuronal cells make neurons specifically sensitive to perturbation in mitochondria distribution (Kann & Kovacs, 2007; Wang et al ., 2009). The absence of mitochondria from axon terminals results in synaptic dysfunction in flies (Stowers et al ., 2002).…”

“…Numerous data showed the crucial role of DLP1 not only in synaptic plasticity but also for neuronal death through DLP1's effects on mitochondrial morphology (Ko et al ., 2016; Li et al ., 2016; Wang et al ., 2016). DLP1‐null mice display embryonic defects in neuronal development associated with dramatic decreases in ATP production and impaired apoptosis (Wang et al ., 2009). In addition, postnatal deletion of DLP1 in the cerebellum results in gradual neurodegeneration over 4–6 months (Kageyama et al ., 2012).…”

“…In Alzheimer's disease (AD) brains, increased level of mitochondrial DLP1 is a primary factor for altered balance in mitochondrial division and fusion, which is likely an important mechanism leading to synaptic loss and neural dysfunction (Wang et al ., 2009). In Huntington's disease (HD), aberrant mitochondrial function has been postulated to critically contribute to striatal degeneration, and inhibitor of DLP1 corrected defects in mitochondrial function and reduced cell death in multiple HD cell models derived from either mice or patients (Guo et al ., 2013).…”

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

“…21 For example, peroxynitrite also causes rapid DRP1 S616 phosphorylation that promotes its translocation to mitochondria and organelle division. 21,22 In mitotic cells, DRP1 S616 phosphorylation is mediated by Cdk1/cyclinB1 and synchronizes mitochondrial division with cell division. 23 Interestingly, DRP1 is S616 hyperphosphorylated in AD brains, suggesting that this event might contribute to mitochondrial fragmentation in the disease.…”

“…23 Interestingly, DRP1 is S616 hyperphosphorylated in AD brains, suggesting that this event might contribute to mitochondrial fragmentation in the disease. 21,22 A recent report indicates that Cdk5/p35 is responsible for DRP1 S616 phosphorylation, 24 and notably aberrant Cdk5/p35/p25 signaling is associated with AD pathogenesis. 25 Thus, we explored here the possible role of DRP1 S616 hyperphosphorylation in Ab-and peroxynitrite-mediated mitochondrial fragmentation.…”