ARTICLE

https://doi.org/10.1038/s41467-020-19205-x OPEN Intellectual disability-associated factor Zbtb11 cooperates with NRF-2/GABP to control mitochondrial function

Brooke C. Wilson 1,3, Lena Boehme 1,3, Ambra Annibali1,3, Alan Hodgkinson 1, Thomas S. Carroll2, ✉ Rebecca J. Oakey 1 & Vlad C. Seitan 1

1234567890():,; Zbtb11 is a conserved mutated in families with hereditary intellectual disability. Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches, here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of nuclear respiratory factor 2 (NRF-2) to its target promoters, activating a subset of nuclear with roles in the biogenesis of and the mitoribosome. Genetic inactivation of Zbtb11 resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human muta- tions showed these have a destabilising effect on the , resulting in reduced Zbtb11 dosage, downregulation of its target genes, and impaired complex I biogenesis. Our study establishes Zbtb11 as an essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and may help to under- stand the aetiology of Zbtb11-associated intellectual disability.

1 Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK. 2 Bioinformatics Resource Centre, The Rockefeller University, ✉ New York, NY 10065, USA. 3These authors contributed equally: Brooke C. Wilson, Lena Boehme, Ambra Annibali. email: [email protected]

NATURE COMMUNICATIONS | (2020) 11:5469 | https://doi.org/10.1038/s41467-020-19205-x | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19205-x

he biochemical energy contained within nutrients is cap- identified ZBTB11 as an essential , indicating that this factor Ttured through the process of cellular respiration, which plays fundamental cellular roles. Consistent with this notion, all culminates in the production of ATP through oxidative ZBTB11 mutations reported so far have been missense mutations phosphorylation (OXPHOS) in mitochondria1. OXPHOS is that are not predicted to cause complete loss of function, sug- fuelled by a chain of redox reactions in which electrons are gesting that the disease may be the result of a partial impairment transferred along an (ETC) that com- of otherwise essential functions carried out by Zbtb11. However, prises four complexes (I–IV) localised to the mitochondrial inner what these functions might be has remained unknown. membrane2. Three of the ETC complexes (I, III and IV) couple Here, we investigate the cellular and molecular functions of substrate oxidation with proton extrusion from the mitochondrial Zbtb11 and find that it is a key regulator of mitochondrial matrix into the intermembrane space, thus creating an electro- function. We show that Zbtb11 controls the -specific chemical gradient across the mitochondrial inner membrane, recruitment of NRF-2/GABP, but not NRF-1, to activate a sub- which forces protons back into the matrix mainly through set of nuclear-encoded genes with roles in the biogenesis of complex V (ATP synthase), driving the synthesis of ATP3. Tis- OXPHOS complex I and the mitoribosome. Genetic inact