Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1

Abstract

A defining feature of mitochondria is their maternal mode of inheritance. However, little is understood about the cellular mechanism through which paternal mitochondria, delivered from sperm, are eliminated from early mammalian embryos. Autophagy has been implicated in nematodes, but whether this mechanism is conserved in mammals has been disputed. Here, we show that cultured mouse fibroblasts and pre-implantation embryos use a common pathway for elimination of mitochondria. Both situations utilize mitophagy, in which mitochondria are sequestered by autophagosomes and delivered to lysosomes for degradation. The E3 ubiquitin ligases PARKIN and MUL1 play redundant roles in elimination of paternal mitochondria. The process is associated with depolarization of paternal mitochondria and additionally requires the mitochondrial outer membrane protein FIS1, the autophagy adaptor P62, and PINK1 kinase. Our results indicate that strict maternal transmission of mitochondria relies on mitophagy and uncover a collaboration between MUL1 and PARKIN in this process.DOI: http://dx.doi.org/10.7554/eLife.17896.001

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

“…In contrast, Parkin KO rats do not exhibit significant PD-related pathology due to probable redundancy of E3 ubiquitin ligases, for example MUL1 [26].…”

“…This is particularly intriguing, as dysregulated iron metabolism has been linked to neurodegenerative disease and clinical trials with deferiprone and PD are currently underway. It should be noted that the signalling pathway regulating deferiprone-induced mitophagy remains to be elucidated and it will be interesting to test the contribution of other ubiquitin E3 ligases, such as the recently described MUL1 E3 ligase [26]. Similarly ubiquitin can be phosphorylated at several other sites and their relevance to mitophagy and the identity of the upstream kinases regulating these residues remains unknown [36].…”

“…It has recently been reported that the mitochondrial ubiquitin ligase 1 (MUL1; also known as MULAN and MAPL) functions with Parkin to regulate degradation of paternal mitochondria from sperm, but the mechanism by which MUL1 induces mitophagy is unknown [26]. Rab GTPase proteins have also been implicated in mitophagy, and two RAB-GAPs (TBC1D15 and TBC1D17) modulate the activity of Rab7 to regulate encapsulation of damaged mitochondria by the autophagosome [27].…”

Oocyte mitochondria: role on fertility and disease transmission

“…In addition, the lower content of mtDNA per mitochondrion together with decreased fusion likely prevent organelle complementation and enhance detection and elimination of dysfunctional mitochondria with mutant molecules. In support of this, mitophagy underpins elimination of all paternal mitochondria shortly after fertilization (Rojansky et al, 2016). Paternal mitochondria lose ΔΨm after entering the oocyte, which seems to be the trigger for mitochondrial degradation.…”

“…Paternal mitochondria lose ΔΨm after entering the oocyte, which seems to be the trigger for mitochondrial degradation. As a consequence, this recruits PARKIN and MUL1 to paternal mitochondria, which are tagged for degradation in lysosomes by ubiquitination (Sutovsky et al, 1999;Al Rawi et al, 2011;Boucret et al, 2015;Rojansky et al, 2016). Figure 2.…”