Electron transport chain biogenesis activated by a JNK-insulin-Myc relay primes mitochondrial inheritance inDrosophila

Abstract

SUMMARYOogenesis features an enormous increase in mitochondrial mass and mtDNA copy number, which are required to furnish mature eggs with adequate mitochondria and to curb the transmission of deleterious mtDNA variants. Quiescent in dividing germ cells, mtDNA replication initiates upon oocyte determination in the Drosophila ovary, which necessitates active mitochondrial respiration. However, the underlying mechanism for this dynamic regulation remains unclear. Here, we show that an feedforward insulin-Myc loop promotes mitochondrial respiration and biogenesis by boosting the expression of electron transport chain subunits and factors essential for mtDNA replication and expression, and mitochondrial protein import. We further reveal that transient activation of JNK enhances the expression of insulin receptor and initiates the insulin-Myc signaling loop. Importantly, this signaling relay ensures sufficient mtDNA in eggs and limits the transmission of a deleterious mtDNA mutation. Our study demonstrates cellular mechanisms that couple mitochondrial biogenesis and inheritance with oocyte development.

Nutrient status shapes selfish mitochondrial genome dynamics across different levels of selection

“…To obtain relative copy number, raw mtDNA copy number across each nuclear genotype was normalized to that of the wildtype controls. In homoplasmic animals, we observed lower mtDNA copy number upon loss of insulin signaling, whether by daf-2 mutation ( Figure 3G and Figure 3—figure supplement 1G ) or by knockdown of daf-2 gene expression ( Figure 3H ), consistent with previous work in Drosophila ( Wang et al, 2019 ). Loss of DAF-16 partially but significantly rescued copy number ( Figure 3G,H and Figure 3—figure supplement 1G ).…”

“…Although the molecular basis for germline purifying selection against ∆mtDNA is unknown, recent work in Drosophila has shown that mitochondrial protein synthesis in oocytes is localized around healthy mitochondria, providing a selection advantage for genomes that lack deleterious mutations ( Zhang et al, 2019 ). Intriguingly, the same group also recently found that insulin signaling mediates purifying selection against a deleterious mtDNA variant in Drosophila eggs in a putatively FoxO-dependent manner ( Wang et al, 2019 ), providing a potential basis by which maternal diet influences purifying selection between parent and embryo, as we observed ( Figure 3B, C ). Whether similar mechanisms underlie germline purifying selection against ∆mtDNA in C. elegans remains to be explored.…”

Mechanical activation of mitochondrial energy metabolism during cell differentiation

“…How mitochondrial energy metabolism is activated during cell differentiation in most developmental processes is unknown. Previous studies uncovered that OXPHOS is transcriptionally activated during differentiation of the Drosophila female germline cyst (Figure 1, A and B) ( 3, 4 ). In the Drosophila germarium, a cystoblast generated from asymmetric division of a germline stem cell undergoes 4 rounds of incomplete cytokinesis to form a cyst with 16 interconnected germ cells.…”

“…A JNK-induced insulin-Myc feedforward loop activates the transcription of OXPHOS genes in differentiating cysts ( 3 ). When N signaling was inhibited in pFCs, both JNK and OXPHOS activities were downregulated in differentiating cysts (Fig.…”

“…JNK-induced OXPHOS supports mtDNA replication during Drosophila oogenesis and maintains fertility ( 3 ). Consistent with our proposal that Tmc maintains cytosolic Ca 2+ to activate JNK and OXPHOS, Tmc RNAi, Fray RNAi or PV overexpression markedly impaired mtDNA replication in the germline and caused reduced egg hatching rate (Fig.…”