Abstract

The C. elegans germline recapitulates mammalian stem cell niches and provides an effective platform for investigating key aspects of stem cell biology. However, the molecular and physiological requirements for germline stem cell homeostasis remain largely elusive. Here, we report that mitochondrial biogenesis and function are crucial for germline stem cell identity. We show that general transcription activity in germline mitochondria is highly compartmentalized, and determines mitochondrial maturation. RPOM-1, the mitochondrial RNA polymerase, is differentially expressed as germ nuclei progress from the distal to the proximal gonad arm to form oocytes. Mitochondria undergo changes from globular to tubular morphology and become polarized, as they approach the proximal gonad arm. Notably, this mitochondrial maturation trajectory is evolutionarily conserved. We find that a similar transition and temporal mitochondrial RNA polymerase expression profile characterizes differentiation of mammalian stem cells. In C. elegans, ATP, and ROS production increases sharply during maturation. Impaired mitochondrial bioenergetics causes gonad syncytium tumor formation by disrupting the balance between mitosis and differentiation to oocytes, which results in a marked reduction of fecundity. Consequently, compensatory apoptosis is induced in the germline. Sperm-derived signals promote mitochondrial maturation and proper germ cell differentiation via the MEK/ERK kinase pathway. Germ cell fate decisions are determined by a crosstalk between Insulin/IGF-1 and TGF-β signaling, mitochondria and protein synthesis. Our findings demonstrate that mitochondrial transcription activity determines a shift in mitochondrial bioenergetics, which in turn regulates germline stem cell survival and differentiation. Perturbation of mitochondrial transcription hinders proper germ cell differentiation and causes germline tumor development.

Highlights

  • In adult Caenorhabditis elegans animals, somatic cells are postmitotic and terminally differentiated

  • We find that perturbations in general mitochondrial transcription and mitochondrial bioenergetics reduces fecundity and causes sterility

  • We found that reporter animals with ifet-1 (RNAi)-mediated knockdown of hmg-5, rpom-1, and tfbm-1 compromised mitochondrial function, as evidenced by a decrease in TMRE (Tetramethylrhodamine, ethyl ester, perchlorate) and MitoTracker Red CMH2XROS stainings, as well as a reduction in ATP levels (Fig. S2B-D)

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Summary

Introduction

In adult Caenorhabditis elegans animals, somatic cells are postmitotic and terminally differentiated. Germ cells are topologically isolated from surrounding somatic tissues and are enclosed in two U-shaped gonads. At the distal tip each gonad, the distal tip cell (DTC), a somatic cell of mesenchymal origin, preserves the mitotic identity of nearby germ cell nuclei through GLP-1 (Notch)/LAG-2 (Delta) signaling. The DTC forms a plexus that surrounds adjacent nuclei [1]. The majority of germline nuclei divide once within the proliferative region [2]. Upon escaping from DTC’s vicinity, they invariably progress toward meiosis I (pachytene, diplotene, and diakinesis), become enclosed by a cell membrane after the gonad turn and form oocytes, which are fertilized upon reaching the spermatheca in the proximal arm [3, 4]. The C. elegans germline shares several features analogous to mammalian stem cell niches; providing an effective platform toward the delineation of cellular and molecular mechanisms underlying stem cell fate [5]

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