Biology subjects

Townsend, B.

Publications and source records attributed to Townsend, B..

3 recordsLinked to original sources

bioRxiv2026

Germline mitophagy selectively eliminates deleterious mitochondrial DNA across generations

Faithful transmission of genetic information through the immortal germline is essential for organismal health and species survival, yet how mutant mitochondrial genomes (mtDNAs) are selectively eliminated across generations remains unclear. Here, we show that germline mitophagy functions as a mutation-responsive surveillance system that selectively eliminates mutant mtDNAs and shapes inheritance across generations. In C. elegans, mitochondria enriched for mutant mtDNAs are selectively removed in the maternal germline prior to oocyte fertilization via PINK1/Parkin-dependent and BNIP3-mediated mitophagy pathways activated by mtDNA defects. Germline mitophagy declines with age, resulting in offspring that inherit increased burdens of mutant mtDNAs. Conversely, enhancing mitophagy within germ cells restricts the transmission of deleterious genomes in a compounding manner, ultimately driving their complete elimination from the matrilineal lineage. Together, our findings demonstrate that germline mitophagy is a critical determinant of intergenerational mitochondrial genome inheritance, establishing its role in restricting the transmission of defective genetic information.

Cell Biology↗

bioRxiv2024

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both basal and induced mitophagy. Disruption of the phosphatase activity of PPTC7 is not required for BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-NIX/BNIP3 and PPTC7-FBXL4 interactions and their disruption interferes with both NIX/BNIP3 degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts NIX/BNIP3-induced mitophagy.

cell biology↗

bioRxiv2022

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Cells selectively remove damaged or excessive mitochondria through mitophagy, a specialized form of autophagy, to maintain mitochondrial quality and quantity. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation, and mitochondrial damage. However, the mechanisms by which cells remove specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box protein ubiquitin ligase complex, localizes to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that, unlike wild-type FBXL4, pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13), do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism that actively suppresses mitophagy via preventing NIX and BNIP3 accumulation and propose that excessive basal mitophagy in the FBXL4-associated mtDNA depletion syndrome is caused by dysregulation of NIX and BNIP3 turnover. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/511867v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c97f6org.highwire.dtl.DTLVardef@1bca5a3org.highwire.dtl.DTLVardef@1e9419org.highwire.dtl.DTLVardef@18d28a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗