Miyuki Sato

Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy-mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady-state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.

The mitochondrial genome is believed to be maternally inherited in many eukaryotes. Sperm-derived paternal mitochondria enter the oocyte cytoplasm upon fertilization and then normally disappear during early embryogenesis. However, the mechanism responsible for this clearance has been unknown. Here, we show that autophagy, which delivers cytosolic components to lysosomes for degradation, is required for the elimination of paternal mitochondria in Caenorhabditis elegans. Immediately after fertilization, sperm-derived components trigger the localized induction of autophagy around sperm mitochondria. Autophagosomes engulf paternal mitochondria, resulting in their lysosomal degradation during early embryogenesis. In autophagy-defective zygotes, paternal mitochondria and their genome remain even in the first larval stage. Thus, fertilization-triggered autophagy is required for selective degradation of paternal mitochondria and thereby maternal inheritance of mitochondrial DNA.

The mitochondrion is an organelle that has its own DNA (mtDNA). Mitochondria play essential roles in energy production and in various cellular processes such as metabolism and signal transduction. In most animals, including humans, although the sperm-derived paternal mitochondria enter the oocyte cytoplasm after fertilization, their mtDNA is never transmitted to the offspring. This pattern of mtDNA inheritance is well known as "maternal inheritance." However, how the paternal mitochondria and mtDNA are eliminated from the cytoplasm of gametes or zygotes remains an enigma. Recently, a variety of mechanisms, including specific nuclease-dependent systems, ubiquitin-proteasome system, and autophagy have been shown to degrade the paternal mtDNA or the paternal mitochondria themselves in order to prevent paternal mtDNA transmission. In this review, we will address the current state of knowledge of the molecular mechanisms underlying the elimination of paternal mtDNA or mitochondrial structures for ensuring the maternal transmission of mtDNA.

Immunization of BALB/c mice with alum-adsorbed OVA, followed by three bronchoprovocations with aerosolized OVA, resulted in the development of airway hyperresponsiveness (AHR) and allergic inflammation in the lung accompanied by severe infiltration of eosinophils into airways. In this murine asthma model, administration of monoclonal anti-IL-5 Ab before each Ag challenge markedly inhibited airway eosinophilia, but the treatment did not affect the development of AHR. Immunization and aerosol challenges with OVA following the same protocol failed to induce AHR in the mast cell-deficient W/Wv mice, but induced AHR in their congenic littermates, i.e., WBB6F1 (+/+) mice. No significant difference was found between the W/Wv mice and +/+ mice with respect to the IgE and IgG1 anti-OVA Ab responses and to the airway eosinophilia after Ag provocations. It was also found that reconstitution of W/Wv mice with bone marrow-derived mast cells cultured from normal littermates restored the capacity of developing Ag-induced AHR, indicating that lack of mast cells was responsible for the failure of W/Wv mice to develop Ag-induced AHR under the experimental conditions. However, the OVA-immunized W/Wv mice developed AHR by increasing the frequency and Ag dose of bronchoprovocations. The results suggested that AHR could be developed by two distinct cellular mechanisms. One would go through mast cell activation and the other is IgE/mast cell independent but an eosinophil/IL-5-dependent mechanism.