Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Abstract

Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

Lack of FTSH4 Protease Affects Protein Carbonylation, Mitochondrial Morphology, and Phospholipid Content in Mitochondria of Arabidopsis: New Insights into a Complex Interplay

“…7B). Several recent findings point to an essential role of yeast and mammalian i-AAA proteases in the mitochondrial QC at the organellar level (Stiburek et al, 2012;Li et al, 2015;Qi et al, 2016). To look into a putative role of FTSH4 in plant mitochondrial dynamics, we first examined the mitochondrial morphology of wild-type and ftsh4-1 plants grown under LD at 22°C (no visible phenotype) and LD at 30°C (visible phenotype) transformed with a construct expressing mitochondria-targeted GFP under the control of the CaMV 35S promoter.…”

Mutations of mitochondrial DNA are not major contributors to aging of fruit flies

“…Mutations in several mitochondrial proteins, including mRpS12, ANT, citrate synthase, and dYme1L, are known to make flies sensitive to mechanical stress (a.k.a. bang-sensitive) ( 48 , 49 ). The impairment of mitochondrial function is believed to lead to neuronal hyperexcitability as these phenotypes can be suppressed by anticonvulsants ( 49 ).…”

Mitochondrial cereblon functions as a Lon-type protease

“…This is a complex form of a late-onset progressive neurodegenerative disorder which involves progressive spasticity, epilepsy, and ID 41 . In Drosophila melanogaster , i-AAA deletion mutants display increased ROS levels, abnormal mitochondria, and neurodegeneration 42 . Moreover, decreased Lon protease expression, at both the RNA and protein level, has been found in a patient with SPG13, one type of an autosomal dominat form of hereditary spastic paraplegia.…”