Aims: Mitofusin (Mfn)2 redundantly promotes mitochondrial outer membrane tethering and organelle fusion with Mfn1, and uniquely functions as the mitochondrial receptor for Parkin during PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy. Selective deletion of Mfn2 with retention of Mfn1 preserves mitochondrial fusion while rendering damaged mitochondria resistant to normal quality control culling mechanisms. Consequently, neuron and cardiomyocyte-specific Mfn2 gene ablation is associated with accumulation of damaged mitochondria and organ dysfunction. Here, we determined how mitochondrial DNA (mtDNA) damage contributes to cardiomyopathy in Mfn2-deficient hearts. Results: RNA sequencing of Mfn2-deficient hearts revealed increased expression of some nuclear-encoded mitochondrial genes, but mitochondrial-encoded transcripts were not upregulated in parallel and mtDNA content was decreased. Ultra-deep sequencing of mtDNA showed no increase in single nucleotide mutations, but copy number variations representing insertion-deletion (in-del) mutations were induced over time by cardiomyocyte-specific Mfn2 deficiency. Double-strand mtDNA breaks in the form of in-dels were confirmed by polymerase chain reaction, and in the form of linear mitochondrial genomes were identified by southern blot analysis. Linearization of Drosophila cardiomyocyte mtDNA using conditional cardiomyocyte-specific expression of mitochondrial targeted XhoI recapitulated the cardiomyopathy of Mfn2-deficient mouse hearts. Innovation: This is the first description of mitochondrial genome linearization as a causative factor in cardiomyopathy. Conclusion: One of the consequences of interrupting mitochondrial culling by the PINK1-Mfn2-Parkin mechanism is an increase in mtDNA double-stranded breaks, which adversely impact mitochondrial function and DNA replication.

Background Despite the prevalence and consequences of distal radius fracture (DRF), there is limited research that analyzes the effects of demographic factors and comorbidities as they relate to pain, perceived disability, and functional outcomes. Methods All data for this study were examined retrospectively within an established clinical database. Patients with DRF were evaluated during their first and final visits with a criterion-based numeric pain scale (CR12), the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire, and a global rate of change scale to assess outcomes of pain, perceived disability, and function, respectively. Results The number of days between injury and initial therapy evaluation were inversely correlated with changes in perceived pain and perceived disability (r =−0.315, p =0.000; r =−0.348, p =0.000). In addition, moderate and statistically significant correlations were noted between work status and average CR12 and DASH scores at final re-evaluation (r =0.392, p =0.000, r =0.473, p =0.000). No significant relationships were noted between additional demographic factors or comorbidities and pain, perceived disability, or function during statistical analysis. Conclusions Patients without diabetes, hypertension, or depression and those who were not smokers had better outcomes in terms of pain, perceived disability, and function in this study. In addition, earlier timing of initial evaluation after injury and full duty work status were significantly related to improvement in pain and perceived disability. Timing of initiation of therapy and return to work are suggested as avenues for future research.Keywords Distal radius fracture . Outcomes . Comorbidities . Demographic factors Distal radius fracture (DRF) can have a severe impact on a person's quality of life by limiting range of motion in the wrist and the ability to complete daily tasks such as dressing, toileting, grooming, and feeding. When a person sustains a DRF, the primary symptoms include edema, pain, and deformity, along with poor range of motion, strength, and dexterity [10]. DRF accounts for one sixth of all fractures in patients over the age of 50 and are the most frequent fractures in the upper limb [1]. Furthermore, up to one fifth of all patients with a DRF have been reported to experience residual symptoms such as pain, nerve symptoms, and disability after 1 year [16]. Despite the prevalence and consequences of this diagnosis, there is limited research that analyzes the effects of demographic factors and comorbidities as they relate to pain, perceived disability, and functional outcomes following DRF.Numerous demographic factors and comorbidities have been previously suggested as intervening variables in the study of fracture outcomes. Gender and age have been identified as variables that may affect the healing process [14,18], while earlier return to function has been correlated with both injury to the dominant hand [2,3] and earlier referral to therapy [27]. Comorbidities including depression, smoking,...

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