Abstract
Fanconi anemia (FA) is a rare genetic disorder associated with bone-marrow failure, genome instability and cancer predisposition. Recently, we and others have demonstrated dysfunctional mitochondria with morphological alterations in FA cells accompanied by high reactive oxygen species (ROS) levels. Mitochondrial morphology is regulated by continuous fusion and fission events and the misbalance between these two is often accompanied by autophagy. Here, we provide evidence of impaired autophagy in FA. We demonstrate that FA cells have increased number of autophagic (presumably mitophagic) events and accumulate dysfunctional mitochondria due to an impaired ability to degrade them. Moreover, mitochondrial fission accompanied by oxidative stress (OS) is a prerequisite condition for mitophagy in FA and blocking this pathway may release autophagic machinery to clear dysfunctional mitochondria.
Highlights
Fanconi anemia (FA) is a rare genetic disorder associated with bone-marrow failure, genome instability and cancer predisposition [1]
We recapitulated these results in HEK cells converted to FA-like phenotype by siRNA knock down, wherein we observed fewer mitochondria with higher average volumes in control scRNA transfected vs. FA-like cells (Supplementary Figure S1B, S1C)
The current study provides the first evidence of mitochondrial fission-dependent impaired mitophagy in FA
Summary
FA is a rare genetic disorder associated with bone-marrow failure, genome instability and cancer predisposition [1]. The current state of knowledge on FA pathway relies on at least 16 genes corresponding to the FA genetic subgroups FA-A –Q and several FA-like genes [2]. Biallelic mutations in any one of these genes except for the X-linked FANCB, leads to FA. Another line of studies, dating back to 1980’s, has provided consistent evidence for a role of oxidative stress (OS) in FA phenotype, such as excess oxygen sensitivity [3,4,5], accumulation of oxidative DNA damage and other anomalies of RedOx endpoints [6, 7]. Direct implications of FA proteins in RedOx pathways have been reported [8]. Recent observations from our group and others of morphological changes in FA mitochondria accompanied by significant reduction in ATP synthesis, low mitochondrial membrane potential (ΔΨm), and decreased respiration capacity, suggest mitochondrial dysfunction (MDF) in FA [9]
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