Golgi-dependent copper homeostasis sustains synaptic development and mitochondrial content

Cortnie Hartwig, Gretchen MacÍas Méndez, Shatabdi Bhattacharjee, Alysia D. Vrailas-Mortimer, Stephanie A. Zlatic, Amanda A.H. Freeman, Avanti Gokhale, Mafalda Concilli, Erica Werner, Christie Sapp Savas, Samantha Rudin-Rush, Laura Palmer, Nicole Shearing, Lindsey Margewich, Jacob McArthy, Savanah Taylor, Blaine Roberts, Vladimir Lupashin, Roman S. Polishchuk, Daniel N. CoxRamon A. Jorquera, Victor Faundez

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the conserved oligomeric Golgi (COG) complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses.

Original languageEnglish
Pages (from-to)215-233
Number of pages19
JournalJournal of Neuroscience
Issue number2
Publication statusPublished - 13 Jan 2021


  • ATP7A
  • Copper
  • Golgi
  • Menkes
  • Mitochondria
  • Wilson

ASJC Scopus subject areas

  • General Neuroscience


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