Local translation at mitochondria in neurons

• Applicant: Professorin Dr. Angelika Harbauer
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 453679203

• Final Report Year: 2024

Final Report Abstract

Mitochondria are the power house of the cell and are a major contributor to the ability of nerve cells to process information in the brain. They influence neuronal health not only by providing energy in the form of ATP, but also store Ca2+ ions, which have a crucial signalling role in neuronal signalling. However, damaged mitochondria can actually be harmful to the cell and need to be removed from the cell by a specialized process called mitophagy. One executor of this program is the protein PINK1, and mutations in the gene encoding PINK1 lead to hereditary forms of Parkinson’s disease. We had previously shown that the mRNA derived from the PINK1 gene needs to be transported by association to mitochondria in order to serve as a local seed for the production of PINK1 protein. This occurs by binding to a complex containing the mitochondrial protein SYNJ2BP. In this project we have evaluated the role of loss of PINK1 interaction with mitochondria on neuronal functions and determined where the production of PINK1 takes places. Two major findings have emerged: (1) Loss of SYNJ2BP alters the ability of neurons to store Ca2+ ions, which impact neuronal functions, and (2) PINK1 protein is translated at ER-localized ribosomes as soon as its mRNA is uncoupled from its mitochondria anchoring place. The first finding can help us to understand, how mitochondria and their positioning in neurons alters the ability of a neuron to signal to its neighbour. This is important in the light of the ability of Ca2+ overload to kill neurons, particularly in the context of neurodegenerative diseases, where Ca2+ dysregulation is frequently observed. Modulation of the neuronal Ca2+ fluxes could potentially prolong neuronal survival and ameliorate disease processes associated with neuron loss. The second finding adds molecular detail to the mechanism involved in activating the crucial quality sensor PINK1. The necessity to untether the Pink1 mRNA and to translate PINk1 protein on an organellar membrane further away from the mitochondrial import machinery may serve to allow partial folding of the PINK1 precursor protein, which is important for its partial import into mitochondria. We have observed a failure to untether Pink1 upon disturbance of cellular signalling by the presence of the Alzheimer’s disease risk factor ApoE4, which led to an inability of neurons to cope with mitochondrial stress. This provides a mechanistic link between ApoE4 and the commonly observed accumulation of damaged mitochondria in Alzheimer’s disease.

Publications

• Analysis of Mitochondria by Single-Organelle Resolution. Annual Review of Analytical Chemistry, 15(1), 1-16.
  Harbauer, Angelika B.; Schneider, Annika & Wohlleber, Dirk
  
• Live-Cell Imaging of RNA Transport in Axons of Cultured Primary Neurons. Methods in Molecular Biology, 225-237. Springer US.
  Hees, J. Tabitha & Harbauer, Angelika B.
  
• Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective. Biomolecules, 12(11), 1595.
  Hees, Jara Tabitha & Harbauer, Angelika Bettina
  
• Microfluidics-Assisted Selective Depolarization of Axonal Mitochondria. Journal of Visualized Experiments(186).
  Wanderoy, Simone; Rühmkorf, Alina & Harbauer, Angelika B.
  
• Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy. Autophagy, 18(12), 3048-3049.
  Harbauer, Angelika B. & Schwarz, Thomas L.
  
• Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy. Neuron, 110(9), 1516-1531.e9.
  Harbauer, Angelika B.; Hees, J. Tabitha; Wanderoy, Simone; Segura, Inmaculada; Gibbs, Whitney; Cheng, Yiming; Ordonez, Martha; Cai, Zerong; Cartoni, Romain; Ashrafi, Ghazaleh; Wang, Chen; Perocchi, Fabiana; He, Zhigang & Schwarz, Thomas L.
  
• Role of Mitochondria–ER Contact Sites in Mitophagy. Biomolecules, 13(8), 1198.
  Rühmkorf, Alina & Harbauer, Angelika Bettina
  
• Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons. Nature Metabolism, 6(3), 514-530.
  Hees, J. Tabitha; Wanderoy, Simone; Lindner, Jana; Helms, Marlena; Murali, Mahadevan Hariharan & Harbauer, Angelika B.
  
• The role of mitochondrial RNA association for mitochondrial homeostasis in neurons. Biochemical Journal, 481(3), 119-139.
  Segura, Inmaculada & Harbauer, Angelika