PPR-proteins, which are implicated in the neurodegenerative disease Leigh Syndrome, reveal a role for mitochondria in attenuating BMP-signaling. Nele Haelterman¹, Manish Jaiswal², Berrak Ugur¹, Hector Sandoval², Ke Zhang³, Taraka Donti², Brett Graham², Vafa Bayat¹, Shinya Yamamoto^1,2, Hugo Bellen^1,2,3,4. 1) Program in Developmental Biology; 2) Department of Molecular and Human Genetics; 3) Structural and Computational Biology & Molecular Biophysics Graduate Program; 4) Howard Hughes Medical Institute, Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030.

   In a forward genetic screen designed to isolate novel loci whose loss causes neuronal demise, we identified loss-of-function mutations in dPPR, a homolog of the human leucine-rich pentatricopeptide repeat containing protein (LRPPRC). Mutations in LRPPRC result in mitochondrial (mt) dysfunction and Leigh Syndrome, a childhood neurometabolic disorder. LRPPRC is a member of the pentatricopeptide repeat-containing (PPR-)protein family that is involved in regulating mt-RNA-polyadenylation and -stability. Bicoid stability factor (bsf) and dPPR are the two Drosophila homologs of LRPPRC. Both proteins localize to mitochondria. We found that dPPR is required to maintain complex I and IV activity within the mt respiratory chain, whereas loss of bsf severely impairs the function of complexes I and III. Our data suggest that dPPR and Bsf coordinately regulate respiratory chain activity. This hypothesis is supported genetically, since simultaneous loss of bsf and dPPR leads to enhanced lethality. To understand how PPR-proteins affect neuronal function and maintenance, we assessed the effects of loss of dPPR or bsf in the adult eye and the third instar larval neuromuscular junction (NMJ). In the eye, homozygous mutant dPPR or bsfclones display severe degeneration upon aging. At the NMJ, loss of either protein leads to severe overgrowth, a phenotype that seems to be due to hyperactivation of the BMP pathway. We are currently investigating how mt proteins can modulate the activity of this neuronal growth-regulating pathway. Our results would help define the role of mitochondria in intercellular signaling during neuronal development and uncover novel insights into the molecular and cellular aspects of Leigh Syndrome.