Investigating the AMPK-MFF pathway to modulate mitochondrial dynamics as a target for neuroprotection

Cellular hallmarks of neurodegenerative diseases include loss of synapses, neuronal death, inflammation, energy homeostasis defects, oxidative stress, mitochondrial dysfunction, and aberrant proteostasis. AMP-activated kinase (AMPK) maintains energy homeostasis by responding to fluctuating ATP levels, with diverse targets ranging from changing the transcriptional program, promoting glucose uptake, inhibiting protein synthesis, inducing mitochondrial fission, mitophagy and autophagy. Evidence indicates that AMPK is hyperactivated in Alzheimer’s disease (AD), and amyloid-β (Aβ) can activate AMPK, leading to mitochondrial fragmentation, mitophagy, and spine loss. In a variety of in vitro and in vivo neurodegenerative models, reducing mitochondrial fragmentation has been shown to be neuroprotective. A key mitochondrial target of AMPK is mitochondrial fission factor (MFF), which is phosphorylated at Ser155 and Ser172 to promote fission. Here we present MFF as a target of SUMOylation (small ubiquitin-like modifier) at Lys151, which is enhanced upon AMPK phosphorylation of MFF. Using primary hippocampal neurons, we show that MFF SUMOylation is required to maintain mitochondrial size. We find that sustained AMPK activation, using the AMP analog AICAR, induces loss of pre- and post-synaptic markers in primary neurons. Future work will examine the AMPK-MFF pathway as a target to modulate AMPK-dependent synaptic loss, and whether preventing MFF SUMOylation under stress conditions will impair mitochondrial fission and maintain synaptic integrity.