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1. GASZ self-interaction clusters mitochondria into the intermitochondrial cement for proper germ cell development

   https://doi.org/10.1093/pnasnexus/pgad480  

   Miao, Junru; Wang, Chuanyun; Chen, Wei; Wang, Yongsheng; Kakasani, Shalin; Wang, Yuan; Bartolomei, ed., Marisa (January 2024, PNAS Nexus)

   Abstract Mitochondrial features and activities vary in a cell type- and developmental stage-dependent manner to critically impact cell function and lineage development. Particularly in male germ cells, mitochondria are uniquely clustered into intermitochondrial cement (IMC), an electron-dense granule in the cytoplasm to support proper spermatogenesis. But it remains puzzling how mitochondria assemble into such a stable structure as IMC without limiting membrane during development. Here, we showed that GASZ (germ cell-specific, ankyrin repeat, SAM and basic leucine zipper domain containing protein), a mitochondrion-localized germ cell-specific protein, self-interacted with each other to cluster mitochondria and maintain protein stability for IMC assembling. When the self-interaction of GASZ was disrupted by either deleting its critical interaction motif or using a blocking peptide, the IMC structure was destabilized, which in turn led to impaired spermatogenesis. Notably, the blocked spermatogenesis was reversible once GASZ self-interaction was recovered. Our findings thus reveal a critical mechanism by which mitochondrion-based granules are properly assembled to support germ cell development while providing an alternative strategy for developing nonhormonal male contraceptives by targeting IMC protein interactions. 

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2. Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis

   https://doi.org/10.1016/j.devcel.2024.09.004  

   Khatun, Jesminara; Gelles, Jesse D; Chipuk, Jerry Edward (October 2024, Developmental Cell)

   The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondria crosstalk with numerous regulated cell death (RCD) pathways to control the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD, that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery; as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die. 

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3. Influence of Maternal Aging on Mitochondrial Heterogeneity, Inheritance, and Function in Oocytes and Preimplantation Embryos

   https://doi.org/doi:10.3390/genes9050265  

   Woods, D; Khrapko, K; Tilly, J. (February 2018, Genes)

   Contrasting the equal contribution of nuclear genetic material from maternal and paternal sources to offspring, passage of mitochondria, and thus mitochondrial DNA (mtDNA), is uniparental through the egg. Since mitochondria in eggs are ancestral to all somatic mitochondria of the next generation and to all cells of future generations, oocytes must prepare for the high energetic demands of maturation, fertilization and embryogenesis while simultaneously ensuring that their mitochondrial genomes are inherited in an undamaged state. Although significant effort has been made to understand how the mtDNA bottleneck and purifying selection act coordinately to prevent silent and unchecked spreading of invisible mtDNA mutations through the female germ line across successive generations, it is unknown if and how somatic cells of the immediate next generation are spared from inheritance of detrimental mtDNA molecules. Here, we review unique aspects of mitochondrial activity and segregation in eggs and early embryos, and how these events play into embryonic developmental competency in the face of advancing maternal age. 

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4. Lineage‐Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells

   https://doi.org/10.1002/adbi.202200246  

   Capelluto, Fausto; Alberico, Hannah; Ledo‐Hopgood, Paula; Tilly, Jonathan_L; Woods, Dori_C (January 2023, Advanced Biology)

   Abstract In addition to critical roles in bioenergetics, mitochondria are key contributors to the regulation of many other functions in cells, ranging from steroidogenesis to apoptosis. Numerous studies further demonstrate that cell type‐specific differences exist in mitochondria, with cells of a given lineage tailoring their endogenous mitochondrial population to suit specific functional needs. These findings, coupled with studies of the therapeutic potential of mitochondrial transplantation, provide a strong impetus to better understand how mitochondria can influence cell function or fate. Here an inducible mitochondrial depletion modelis used to study how cells lacking endogenous mitochondria respond, on a global protein expression level, to transplantation with lineage‐mismatched (LM) mitochondria. It is shown that LM mitochondrial transplantation does not alter the proteomic profile in nonmitochondria–depleted recipient cells; however, enforced depletion of endogenous mitochondria results in dramatic changes in the proteomic landscape, which returns to the predepletion state following internalization of LM mitochondria. These data, derived from a cell system that can be rendered free of influence by endogenous mitochondria, indicate that transplantation of mitochondria—even from a source that differs significantly from the recipient cell population, effectively restores a normal proteomic landscape to cells lacking their own mitochondria. 

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5. The conserved molting/circadian rhythm regulator NHR-23/NR1F1 serves as an essential co-regulator of C. elegans spermatogenesis

   https://doi.org/10.1242/dev.193862  

   Ragle, James Matthew; Aita, Abigail L.; Morrison, Kayleigh N.; Martinez-Mendez, Raquel; Saeger, Hannah N.; Ashley, Guinevere A.; Johnson, Londen C.; Schubert, Katherine A.; Shakes, Diane C.; Ward, Jordan D. (November 2020, Development)

   null (Ed.)

   In sexually reproducing metazoans, spermatogenesis is the process by which uncommitted germ cells give rise to haploid sperm. Work in model systems has revealed mechanisms controlling commitment to the sperm fate, but how this fate is subsequently executed remains less clear. While studying the well-established role of the conserved nuclear hormone receptor transcription factor, NHR-23/NR1F1, in regulating C. elegans molting, we discovered NHR-23/NR1F1 is also constitutively expressed in developing 1° spermatocytes and is a critical regulator of spermatogenesis. In this novel role, NHR-23/NR1F1 functions downstream of the canonical sex determination pathway. Degron-mediated depletion of NHR-23/NR1F1 within hermaphrodite or male germlines causes sterility due to an absence of functional sperm as depleted animals produce arrested primary spermatocytes rather than haploid sperm. These spermatocytes arrest in prometaphase I and fail to either progress to anaphase or attempt spermatid-residual body partitioning. They make sperm-specific membranous organelles (MOs) but fail to assemble their major sperm protein into fibrous bodies. NHR-23/NR1F1 appears to function independently of the known SPE-44 gene regulatory network, revealing the existence of an NHR-23/NR1F1-mediated module that regulates the spermatogenesis program. 

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