Abstract
The molecular pathology of diseases seen from the mitochondrial axis has become more complex with the progression of research. A variety of factors, including the failure of mitochondrial dynamics and quality control, have made it extremely difficult to narrow down drug discovery targets. We have identified MITOL (mitochondrial ubiquitin ligase: also known as MARCH5) localized on the mitochondrial outer membrane and previously reported that it is an important regulator of mitochondrial dynamics and mitochondrial quality control. In this review, we describe the pathological aspects of MITOL revealed through functional analysis and its potential as a drug discovery target.
Highlights
There are many functional proteins on the mitochondrial outer membrane
MITOL is a mitochondrial membrane-associated RING finger E3 ubiquitin ligase and was initially identified as a regulator of mitochondrial dynamics, which involves two different aspects: the regulation of protein activation by K63 ubiquitin chain attachment and the regulation of proteasome-dependent degradation by K48 ubiquitin chain attachment via ubiquitin signaling on the outer mitochondrial membrane
If the worsening of Alzheimer’s disease (AD) is linked to the reduced MITOL expression, the compounds we have identified may exert a good therapeutic effect on AD
Summary
There are many functional proteins on the mitochondrial outer membrane. Since mitochondrial function is tightly regulated by mitochondrial dynamics, its molecular mechanisms and their association with disease have attracted substantial attention. Growing evidence has shown that E3 ubiquitin ligases are involved in the regulation of mitochondrial functions. MITOL (mitochondrial ubiquitin ligase: known as MARCH5) is a mitochondrial membrane-associated RING finger E3 ubiquitin ligase and was initially identified as a regulator of mitochondrial dynamics, which involves two different aspects: the regulation of protein activation by K63 ubiquitin chain attachment and the regulation of proteasome-dependent degradation by K48 ubiquitin chain attachment via ubiquitin signaling on the outer mitochondrial membrane. A number of MITOL substrates have been identified so far and their association with disease has been suggested. We present the latest findings on MITOL as a potential drug target and its relevance to disease and aging
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