This is a summary of Hees, J.T., Wanderoy, S., Lindner, J., Helms, M., Mahadevan, H.M., Harbauer, A.B. ‘Insulin signaling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons’ which appeared in Nature Metabolism (2024). https://www.nature.com/articles/s42255-024-01007-w
The challenge
In neurodegenerative diseases, the health and function of mitochondria are often not well maintained, leading to mitochondrial dysfunction and, ultimately, cell death. One way to observe mitochondrial health is by looking at PINK1, a short-lived protein. If mitochondria are damaged, PINK1 cannot be imported into the mitochondria to be cleaved and degraded. Instead, it is found on the outer mitochondrial membrane, where it phosphorylates ubiquitin molecules.
We aimed to investigate how insulin and AMP-activated protein kinase (AMPK) signaling regulate mitochondrial Pink1 mRNA localization and PINK1 function. AMPK is an enzyme that helps cells maintain their energy balance; it is activated in response to decreased cellular energy and triggers processes to produce ATP.
Our approach
We used in vitro models, including primary mouse and human iPSC-derived neurons models, and visualized the location of the Pink1 mRNA using a live-cell-imaging suitable reporter. We modulated AMPK and insulin signaling by genetic and pharmacological means and induced insulin resistance by adding the key genetic Alzheimer-21 risk factor apolipoprotein E4 (ApoE4) to cultured neurons to study the relation between insulin and mitochondrial health.
Our findings
Our results suggest that defective insulin signaling will have direct consequences on Pink1 mRNA localization and downstream mitochondrial quality. We found that when inhibiting AMPK by activating the insulin signaling cascade, Pink1 mRNA does not bind to mitochondria, allowing the PINK1 protein to be produced to detect mitochondrial damage. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. These results suggest a mechanistic connection between insulin resistance and mitochondrial dysfunction.
The implications
Our results are currently an in vitro study that allowed us to identify a mechanism used by neurons to match their mitochondrial quality control in neurons to the metabolic state of the body. If this mechanism is also operable in the context of a living organism, it suggests that dietary interventions or the repurposing of diabetes medication could be used to activate mitochondrial quality control in the aging or diseased brain to improve mitochondrial health.
Creating SyNergies
This study was led by Angelika Harbauer (TUM / Max Planck Institute for Biological Intelligence). We are currently using the power of the SyNergy Nanoscale hub to catch the location of PINK1 protein biogenesis by correlative life and electron microscopy (CLEM). We also explore the repertoire of mitochondrially associated RNAs in vivo in collaboration with Thomas Misgeld.
