ABSTRACT
INTRODUCTION: Acute hepatic porphyrias (AHP) are a rare group of inherited disorders caused by abnormal functioning of the heme synthesis pathway. Patients often present with diffuse abdominal pain, neurologic dysfunction, and hyponatremia. CASE REPORT: We present a case of a 25-year-old female who presented with AHP after implantation of progestin birth control. The patient was confused, markedly tachycardic and hypertensive, and complained of severe abdominal pain. Spot urine ordered during the emergency department workup was later found positive for porphyrins and porphobilinogen (PBG). CONCLUSION: Acute hepatic porphyrias typically present with nonspecific symptoms in young women and are often overlooked in the acute care setting. Spot urine testing for PBG and urine porphyrins should be initiated early in patients with clinical suspicion of AHP.
ABSTRACT
Mitochondria shape cytosolic calcium ([Ca2+]c) transients and utilize the mitochondrial Ca2+ ([Ca2+]m) in exchange for bioenergetics output. Conversely, dysregulated [Ca2+]c causes [Ca2+]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+-induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+]c elevation, but not MCU-mediated Ca2+ uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca2+-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST.
Subject(s)
Calcium/metabolism , Mitochondria/metabolism , Mitochondrial Dynamics , Receptors, G-Protein-Coupled/metabolism , Stress, Physiological , rho GTP-Binding Proteins/metabolism , Animals , HeLa Cells , Humans , Mice , Mice, Mutant Strains , Mitochondria/genetics , Receptors, G-Protein-Coupled/genetics , rho GTP-Binding Proteins/geneticsABSTRACT
Ca2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated in mitochondria. Whether and how these coactive elements interact with MCU have not been established. As an approach toward understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 (Cys-97) to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural, and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca2+]m uptake rate, elevated mROS, and enhanced [Ca2+]m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity.
