GASZ directly recruits MILI to the intermitochondrial cement for piRNA biogenesis and male germ cell development

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Repressing transposable elements via piRNAs represents a critical defense mechanism for germ cells to maintain genomic integrity. The primary piRNA biogenesis largely occurs at intermitochondrial cement (IMC), which is characterized by uniquely clustered mitochondria and ribonucleoproteins as "cementing material." RNA-binding proteins at IMC, such as MILI, are essential for piRNA biogenesis. However, MILI proteins do not possess mitochondrial localization signals; thus, they must rely on other proteins to functionally communicate with IMC. In this study, we identified GASZ as a crucial interacting partner for MILI at IMC from prospermatogonia to spermatocytes. We found that GASZ proteins at mitochondria directly recruited MILI to IMC for piRNA biogenesis. Abolishing GASZ-MILI interaction in the embryonic germ cells reduced fetal piRNA level, increased transposon expression, and compromised spermatogonial and spermatocyte development during the first wave of spermatogenesis. In addition, disrupting GASZ-MILI interaction in adulthood significantly impaired spermatogenesis, with reduced spermatocyte and spermatid formation, proving that MILI and GASZ partner together to regulate steady-state spermatogenesis. Taken together, by revealing critical GASZ-MILI interaction at IMC and defining its impact on spermatogenesis, our findings critically inform how the piRNA biogenesis machinery is constructed via protein interactions to preserve germline DNA integrity for proper germ cell development.

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