Biology subjects

Harbauer, A. B.

Publications and source records attributed to Harbauer, A. B..

7 recordsLinked to original sources

bioRxiv2026

PINK1 stabilizes RMDN3-VAPB interaction without altering the landscape of mito-ER contact sites

Mitochondria-ER contact sites (MERCS) have emerged as central hubs of organellar biology, participating in the exchange of lipids, Ca2+ and even protein precursors. During mitochondrial dysfunction, the contact between the ER-resident protein VAPB and the outer mitochondrial membrane protein RMDN3 (PTPIP51) increases, yet the mechanism stabilizing this connection despite ongoing mitophagy remains to be determined. Here we develop a splitAPEX2 based proximity biotinylation tool to assess the interaction of VAPB and RMDN3. We determine that activation of the mitochondrial depolarization-induced kinase PINK1 leads to phosphorylation of RMDN3 at T160, which is necessary to increase the interaction with VAPB in the presence of mitochondrial depolarization. Mass Spectrometric analysis of the RMDN3-VAPB MERCS proteome reveals that these contacts also include peroxisomal proteins and that the proteomic composition remains stable during mitochondrial depolarization.

cell biology↗

bioRxiv2026

A Na⁺-PINK1 signaling axis couples mitochondrial fission to structural remodeling during synaptic depression

Mitochondrial density in dendrites adapts to the number of synaptic inputs to adequately sustain local ATP and Ca2+ buffering for neuronal signaling. During long-term depression (LTD), synapse elimination is accompanied by activation of caspase-3 through sublethal mitochondria-derived apoptotic signals, driving neurotransmitter receptor internalization and spine shrinking. However, the upstream signals that link synaptic activity to mitochondrial remodeling remain unknown. Here we show that Na+ influx through NMDA receptors depolarizes mitochondria during chemically induced LTD. This triggers stabilization and activation of the PINK1 kinase in a translation-dependent manner, leading to asynchronous mitochondrial fission. Na+ influx and PINK1 are required for cLTD-induced fission, and blocking either Na+ influx or PINK1 prevents caspase-3 activation and spine shrinking in cultured neurons. Together, these findings identify a Na+-PINK1 signaling axis that couples NMDA receptor activity to mitochondrial fission and caspase-3-dependent synapse elimination during LTD, with implications for the homeostatic regulation of synaptic density.

neuroscience↗

bioRxiv2026

Mitochondrial hitch-hiking of Mapt mRNA maintains Tau levels in axons

Hitch-hiking of transcripts on organelles, including mitochondria, has emerged as a common pathway to transport mRNAs into the axon to enable their local translation. However, the extent of mitochondrial mRNA association in vivo has not been established. Here we report the landscape of mitochondrial mRNA association in two nerve tissues, the retinal ganglion cell derived optic nerve and the motor neuron derived part of the sciatic nerve. This revealed astonishing tissue diversity between mitochondria associated mRNAs that can partly be explained by the lack of expression of the mitochondrially anchored RNA-binding protein SYNJ2a in motor neurons. This diversity led us to discover that also MAPT mRNA, encoding the axon-enriched microtubule associated protein Tau, is transported via the mitochondrial RNA anchoring complex SYNJ2a/SYNJ2BP into axons of glutamatergic neurons. Loss of SYNJ2BP prevents axonal localization of MAPT and miss-sorting of Tau, consequently stunting axonal growth in cultured hippocampal neurons. This connects mitochondrial transport to the maintenance of the local cytoskeleton and axonal growth in glutamatergic neurons.

neuroscience↗

bioRxiv2025

Neuronal compartmentalization results in impoverished axonal mitochondria

Mitochondria differ depending on their location within a neuron. Morphological heterogeneity between somatic, dendritic, and axonal mitochondria is well established. Emerging evidence suggests that further specialization is needed to meet the unique demands of different neuronal compartments. However, the molecular and functional diversity of mitochondria within a neuron remains poorly understood. Here, we utilized proteomics in MitoTag mice to profile somatodendritic and axonal mitochondria across four distinct neuron types, thereby generating a compendium of intracellular mitochondrial diversity. Combining proteomics, functional, and immunofluorescence analyses, we demonstrated that axonal mitochondria are not defined by the presence of unique proteins, but rather by the selective loss or preservation of specific pathways compared to their somatodendritic counterparts. This results in "impoverished" axonal mitochondria, which are characterized by diminished mtDNA expression and impaired oxidative phosphorylation yet retain other pathways, such as fatty acid metabolism. Bioinformatic analyses of multiomic data identified local translation as one mechanism underlying compartment-specific diversity. Together, these findings provide a comprehensive in vivo framework for understanding mitochondrial specialization across neuronal compartments.

neuroscience↗

bioRxiv2024

ER-associated biogenesis of PINK1 preprotein for neuronal mitophagy

A central role in mitochondrial quality control is played by the Parkinson-related mitochondrial kinase PINK1, whose mRNA is transported in neurons by mitochondrial hitch- hiking. Using a live-cell imaging assay for the translation of the PINK1 precursor, we show that local translation of PINK1 requires a concerted interplay between mitochondria and the ER in neurons. For efficient translation, the Pink1 mRNA needs to relocate to ribosomes located near endolysosomes and the ER. The ER membrane-tethered chaperone DNAJB6 then shields the PINK1 precursor on transit to mitochondria following the ER-SURF pathway. Loss of DNAJB6 hence leads to persistence of ER/endolysosome-associated PINK1 precursor stores and failure of mitophagy upon mitochondrial damage.

neuroscience↗

bioRxiv2023

Insulin signaling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons

Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 mRNA by tethering it to the mitochondrial surface. Here, we report that inhibition of AMPK by activation of the insulin signaling cascade prevents Pink1 mRNA binding to mitochondria. 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. Interestingly, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin-resistance in vitro by the key genetic Alzheimer-risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signaling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.

neuroscience↗

bioRxiv2021

Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy

PTEN-induced kinase 1 (PINK1) is a very short-lived protein that is required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated with and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane protein Synaptojanin 2 binding protein (SYNJ2BP) and Synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for activation of mitophagy.

neuroscience↗