Structural determinants of mitochondrial STAT3 targeting and function.

Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.

Initial Cervical Spinal Cord Demyelinating Lesions are not Associated with Restless Legs Syndrome in Patients with Multiple Sclerosis.

Purpose: This study aims to determine the prevalence and severity of restless legs syndrome (RLS) in patients with multiple sclerosis (MS) and its association with spinal cord lesions, fatigue, quality of life, and sleep disturbance. Methods: We recruited 222 consecutive MS patients admitted to MS outpatient clinic. Beck's Depression Inventory (BDI), Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and MS Quality of Life-54 (MSQoL-54) questionnaire scores of all patients were measured. Initial cervical spinal cord magnetic resonance imaging (MRI) of the patients at first clinical evaluation for diagnosis was reviewed for accompanying demyelinating lesions. Results: RLS was diagnosed in 53 (23.87%) patients. RLS was associated with poor sleep, worse quality of life, increased fatigue, and depressive mood. The sleep quality index, FSS, and MSQoL-54 physical composite scores significantly correlated with RLS severity (P < 0.001, P = 0.001, P < 0.001, respectively). Of the 200 patients, 127 (63.5%) had spinal cord lesions. 22.83% of the patients with cervical spinal cord lesions had RLS comorbidity. We found no significant difference regarding spinal cord demyelinating lesions between RLS positives and negatives. (P = 0.77). In addition, having multiple spinal cord demyelinating lesions did not differ between the two groups (P = 0.84). Besides, the severity of RLS symptoms did not differ in patients who had a single cervical spinal lesion and those who had multiple lesions (P = 0.35). Conclusion: We have demonstrated the negative impact of comorbid RLS on fatigue, sleep quality, mood, and quality of life in MS patients. However, initial spinal cord lesions did not correlate with RLS comorbidity. The severity of RLS symptoms is associated with poor sleep and physical health.