Abstract
Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA processing, and other biological pathways, rather than “threshold effect” and environmental factors, provide more specific explanation to the aberrant phenotype. Thus, the double hit theory, mutations both in mitochondrial DNA and modifying genes aggravating the symptom, throws new light on mitochondrial dysfunction processes. In addition, mitochondrial retrograde signaling pathway that leads to reconfiguration of cell metabolism to adapt defects in mitochondria may as well play an active role. Here we review selected examples of modifier genes and mitochondrial retrograde signaling in mitochondrial disorders, which refine our understanding and will guide the rational design of clinical therapies.
Highlights
Mitochondria are essential organelles inside cells that are responsible for cellular energy production
Mitochondrial disorders has been linked to an enormous variety of disease, such as mitochondrial encephalomyopathy (MELAS) syndrome, myoclonic epilepsy with ragged red fibers (MERRF) syndrome, LOHN (Leber’s hereditary optic neuropathy), deafness, diabetes, Alzheimer disease, and Parkinson disease (Wallace, 2005)
An identical degree of mitochondrial dysfunction was observed when they compared the cybrids cell lines derived from symptomatic and asymptomatic individuals (Guan et al, 2001). These findings strongly indicate that the m.A1555G mutation as a primary cause of hearing loss and nuclear modifier genes play a role in modulating the phenotypic expression (Guan et al, 2006)
Summary
Mitochondria are essential organelles inside cells that are responsible for cellular energy production. An identical degree of mitochondrial dysfunction was observed when they compared the cybrids cell lines derived from symptomatic and asymptomatic individuals (Guan et al, 2001) These findings strongly indicate that the m.A1555G mutation as a primary cause of hearing loss and nuclear modifier genes play a role in modulating the phenotypic expression (Guan et al, 2006). Raimundo et al showed that increased level of mitochondrial ROS in m.1555A>G cybrids activates the proapoptotic nuclear transcription factor E2F1 in an AMPK dependent manner; and in the animal study by using Tg-mtTFB1 transgenic (to model pathogenesis due to increased mitochondrial12S rRNA methylation), progressive hearing loss was observed associated with tissue-specific upregulation of E2F1, as well as the apoptosis of critical cells in inner ear (Raimundo et al, 2012). This result provides an alternative perspective on the cellular basis of phenotypic heterogeneity in mtDNA diseases
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
