en
  • Deutsch - de
  • English - en
  • About
      About us
        Our Measures
          Members
            Cluster Management
               PhD & Postdoc representatives
                Scientific Advisory Board
                   International cooperation partners
                    Timeline
                       Media Kit
                        Contact
                      • News & Events
                          News
                            Events
                              In the News
                                Open Positions
                              • Research
                                  Publications
                                    Our Research Focus
                                      Technology Hubs
                                        Research Spotlight
                                          Data Management & Sharing
                                            Sustainability Initiative
                                               Code of Conduct
                                            • Science & Society
                                                For Schools & Students
                                                  Public Events
                                                    Podcasts
                                                      Videos
                                                    • Support for Diversity & Equity
                                                        Newcomer Center
                                                          Gender Equality Program
                                                            Early Career Investigator Program
                                                          1. Home
                                                          2. News & Events
                                                          3. News
                                                          4. A mechanistic connection between insulin resistance and mitochondrial dysfunction
                                                          News | 19/03/2024 | Research Spotlight

                                                          A mechanistic connection between insulin resistance and mitochondrial dysfunction

                                                          There is growing evidence that problems with insulin signaling play an important role in the development of neurodegenerative disease, but its exact mechanisms remain unclear. Researchers in a new study focusing on mitochondrial quality control identified a metabolic switch suggesting a mechanistic connection between insulin resistance and mitochondrial dysfunction.  
                                                           Research Spotlight: Photo of the researcher and a quote about the impact of the research

                                                          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.  

                                                          Participating Universities
                                                           LMU logo in white
                                                           TUM logo in white
                                                          Partner Institutions
                                                           Logo DZNE in white
                                                          Helmholtz Munich logo in white 
                                                           Logo Max Planck Gesellschaft 

                                                          SyNergy is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the German Excellence Strategy (EXC 2145 SyNergy – ID 390857198). The Excellence Strategy promotes outstanding research at German universities. 

                                                          Contact

                                                          Munich Cluster for Systems Neurology (SyNergy)

                                                          Feodor-Lynen-Str. 17
                                                          81377 Munich
                                                          +49 (0)89 4400-46497
                                                          yüu;bgybcјuipxјrvDfulyzsmi
                                                          Login for editors
                                                          Imprint | Data-Safety
                                                          en
                                                          • Deutsch - de
                                                          • English - en

                                                          Home

                                                          • About
                                                            • About us
                                                            • Our Measures
                                                            • Members
                                                            • Cluster Management
                                                            •  PhD & Postdoc representatives
                                                            • Scientific Advisory Board
                                                            •  International cooperation partners
                                                            • Timeline
                                                            •  Media Kit
                                                            • Contact
                                                          • News & Events
                                                            • News
                                                            • Events
                                                            • In the News
                                                            • Open Positions
                                                          • Research
                                                            • Publications
                                                            • Our Research Focus
                                                            • Technology Hubs
                                                            • Research Spotlight
                                                            • Data Management & Sharing
                                                            • Sustainability Initiative
                                                            •  Code of Conduct
                                                          • Science & Society
                                                            • For Schools & Students
                                                            • Public Events
                                                            • Podcasts
                                                            • Videos
                                                          • Support for Diversity & Equity
                                                            • Newcomer Center
                                                            • Gender Equality Program
                                                            • Early Career Investigator Program