Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.

Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS). In the inner mitochondrial membrane, the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) exchanges ADP and ATP, enabling OXPHOS. AAC/ANT contains three tightly bound CLs, and these interactions are evolutionarily conserved. Here, we investigated the role of these buried CLs in AAC/ANT using a combination of biochemical approaches, native mass spectrometry, and molecular dynamics simulations. We introduced negatively charged mutations into each CL-binding site of yeast Aac2 and established experimentally that the mutations disrupted the CL interactions. While all mutations destabilized Aac2 tertiary structure, transport activity was impaired in a binding site-specific manner. Additionally, we determined that a disease-associated missense mutation in one CL-binding site in human ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions.

Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant.

The mitochondrial phospholipid cardiolipin (CL) promotes bioenergetics via oxidative phosphorylation (OXPHOS). Three tightly bound CLs are evolutionarily conserved in the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) which resides in the inner mitochondrial membrane and exchanges ADP and ATP to enable OXPHOS. Here, we investigated the role of these buried CLs in the carrier using yeast Aac2 as a model. We introduced negatively charged mutations into each CL-binding site of Aac2 to disrupt the CL interactions via electrostatic repulsion. While all mutations disturbing the CL-protein interaction destabilized Aac2 monomeric structure, transport activity was impaired in a pocket-specific manner. Finally, we determined that a disease-associated missense mutation in one CL-binding site in ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions.

Analysis of Sinus Balloon Catheter Dilation Providers Based on Medicare Provider Utilization and Payment Data.

BACKGROUND: The use of balloon catheter dilation (BCD) to treat chronic rhinosinusitis has increased dramatically since its conception, necessitating further characterization of BCD providers and trends in its usage. Medicare data on BCD providers have made it possible to study recent demographic patterns. There has also been an increase in mid-level providers' scope of otolaryngologic practice that is not well defined. OBJECTIVE: To better understand BCD adoption by studying volume of BCD procedures as well as training, geography, and practice socioeconomic characteristics of BCD providers for Medicare beneficiaries. METHODS: We reviewed Medicare Provider Utilization and Payment Data Public Use Files for 2014 and 2015 for providers with claims for BCD of the sinuses. We extracted provider zip code, state, gender, and number of services per BCD code. We obtained median household income by zip code and geographic region based on US Census Bureau data. Providers were classified using an Internet search to determine practice setting and type of specialty training/certification. RESULTS: In 2014 and 2015, 428 providers performed 42 494 BCDs billed to Medicare beneficiaries. Among BCD providers, 5.1% were female, 98.1% had Doctor of Medicine/Doctor of Osteopathic Medicine credentials, and 1.9% had nurse practitioner/physician assistant credentials. Over the 2-year period, the median number of BCDs was 63 for physicians and 37 for mid-level providers. Fellowship-trained rhinologists performed a median of 38 BCDs over 2 years. The most common subspecialty certification/training was in facial plastics and reconstructive surgery. The majority of providers (63.8%) performed 1 to 99 BCDs over the 2 years. In the South, there were 21.9 BCD procedures performed per 100 000 people compared to 7.3 in the Northeast, 9.3 in the Midwest, and 8.5 in the West. CONCLUSION: There is a large range in total BCD procedures performed by individual providers, and this varies by certain provider characteristics. Mid-level providers have emerged as a significant population performing BCD.

Light-dependent pathways for dopaminergic amacrine cell development and function.

Retinal dopamine is a critical modulator of high acuity, light-adapted vision and photoreceptor coupling in the retina. Dopaminergic amacrine cells (DACs) serve as the sole source of retinal dopamine, and dopamine release in the retina follows a circadian rhythm and is modulated by light exposure. However, the retinal circuits through which light influences the development and function of DACs are still unknown. Intrinsically photosensitive retinal ganglion cells (ipRGCs) have emerged as a prime target for influencing retinal dopamine levels because they costratify with DACs in the inner plexiform layer and signal to them in a retrograde manner. Surprisingly, using genetic mouse models lacking specific phototransduction pathways, we find that while light influences the total number of DACs and retinal dopamine levels, this effect does not require ipRGCs. Instead, we find that the rod pathway is a critical modulator of both DAC number and retinal dopamine levels.