Browsing by Author "Miller, Caroline A."

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    Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
    (Springer Nature, 2023-03-27) Thoudam, Themis; Chanda, Dipanjan; Lee, Jung Yi; Jung, Min-Kyo; Sinam, Ibotombi Singh; Kim, Byung-Gyu; Park, Bo-Yoon; Kwon, Woong Hee; Kim, Hyo-Jeong; Kim, Myeongjin; Lim, Chae Won; Lee, Hoyul; Huh, Yang Hoon; Miller, Caroline A.; Saxena, Romil; Skill, Nicholas J.; Huda, Nazmul; Kusumanchi, Praveen; Ma, Jing; Yang, Zhihong; Kim, Min-Ji; Mun, Ji Young; Harris, Robert A.; Jeon, Jae-Han; Liangpunsakul, Suthat; Lee, In-Kyu; Pathology and Laboratory Medicine, School of Medicine
    Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.
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    Hydrodynamic Isotonic Fluid Delivery Ameliorates Moderate-to-Severe Ischemia-Reperfusion Injury in Rat Kidneys
    (American Society of Nephrology, 2017-07) Collett, Jason A.; Corridon, Peter R.; Mehrotra, Purvi; Kolb, Alexander L.; Rhodes, George J.; Miller, Caroline A.; Molitoris, Bruce A.; Pennington, Janice G.; Sandoval, Ruben M.; Atkinson, Simon J.; Campos-Bilderback, Silvia B.; Basile, David P.; Bacallao, Robert L.; Cellular and Integrative Physiology, School of Medicine
    Highly aerobic organs like the kidney are innately susceptible to ischemia-reperfusion (I/R) injury, which can originate from sources including myocardial infarction, renal trauma, and transplant. Therapy is mainly supportive and depends on the cause(s) of damage. In the absence of hypervolemia, intravenous fluid delivery is frequently the first course of treatment but does not reverse established AKI. Evidence suggests that disrupting leukocyte adhesion may prevent the impairment of renal microvascular perfusion and the heightened inflammatory response that exacerbate ischemic renal injury. We investigated the therapeutic potential of hydrodynamic isotonic fluid delivery (HIFD) to the left renal vein 24 hours after inducing moderate-to-severe unilateral IRI in rats. HIFD significantly increased hydrostatic pressure within the renal vein. When conducted after established AKI, 24 hours after I/R injury, HIFD produced substantial and statistically significant decreases in serum creatinine levels compared with levels in animals given an equivalent volume of saline via peripheral infusion (P<0.05). Intravital confocal microscopy performed immediately after HIFD showed improved microvascular perfusion. Notably, HIFD also resulted in immediate enhancement of parenchymal labeling with the fluorescent dye Hoechst 33342. HIFD also associated with a significant reduction in the accumulation of renal leukocytes, including proinflammatory T cells. Additionally, HIFD significantly reduced peritubular capillary erythrocyte congestion and improved histologic scores of tubular injury 4 days after IRI. Taken together, these results indicate that HIFD performed after establishment of AKI rapidly restores microvascular perfusion and small molecule accessibility, with improvement in overall renal function.
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    Osteocytic perilacunar/canalicular turnover in hemodialysis patients with high and low serum PTH levels
    (Elsevier, 2018-08) Yajima, Aiji; Tsuchiya, Ken; Burr, David B.; Minner, Daniel E.; Condon, Keith W.; Miller, Caroline A.; Satoh, Shigeru; Inaba, Masaaki; Nakayama, Takashi; Tanizawa, Tatsuhiko; Ito, Akemi; Nitta, Kosaku; Anatomy and Cell Biology, IU School of Medicine
    Osteocytic perilacunar/canalicular turnover in hemodialysis patients has not yet been reported. Osteocyte lacunae in lamellar bone and woven bone were classified as eroded surface-, osteoid surface-, and quiescent surface-predominant osteocyte lacunae (ES-Lc, OS-Lc, QS-Lc, respectively) in 55 hemodialysis patients with either high- (n = 45) or low- (n = 10) parathyroid hormone levels, and 19 control subjects without chronic kidney disease. We calculated the area and number of ES-Lc, OS-Lc, and QS-Lc. The mineralized surface on the osteocyte lacunar walls was measured in each group, and compared among the three groups. The shapes of the osteocyte lacunar walls were validated by backscattered electron microscopy. While the number of ES-Lc per bone area (N.ES-Lc/B.Ar) was higher than the number of OS-Lc per bone area (N.OS-Lc/B.Ar) in all groups, N.ES-Lc/B.Ar and N.OS-Lc/B.Ar were greater in high-parathyroid hormone group than in low-parathyroid hormone and control groups. The total volume of ES-Lc per bone area (ES-Lc.Ar/B.Ar) was greater than the total volume of OS-Lc per bone area (OS-Lc.Ar/B.Ar) in both parathyroid hormone groups. However, both lacunar erosion and lacunar formation increased proportionally, suggesting that global coupling between them was maintained. N.ES-Lc/B.Ar was higher in woven bone than in lamellar bone. The rate of OS-Lc stained by tetracycline hydrochloride, the mineralized lacunar surface and the mean area of OS-Lc with Tc obtained from both parathyroid hormone groups were greater than those in the control group. We conclude that osteocytic perilacunar/canalicular turnover is increased in hemodialysis patients with high parathyroid hormone levels. Osteocytic perilacunar/canalicular turnover depends, at least in part, on serum parathyroid hormone level. However, the ideal PTH level for osteocytic perilacunar/canalicular turnover could not be determined but osteocytic osteolysis was predominant in both the high- and low-PTH groups in this study. Thus, attention should be paid to bone loss from the viewpoint of osteocytic perilacunar/canalicular turnover in hemodialysis patients.