Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria

Abstract

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.) O xygen-sensing pathways orchestrate phenotypic adjustments from the cellular to the whole-body level, allowing function and survival under a variety of conditions. 1 The hypoxic response is exquisitely sensitive and dynamic, with relatively small changes in oxygen availability initiating transcriptional and post-transcriptional responses. 2 A fundamental process in this pathway is the ubiquitination and subsequent degradation of the hypoxia-inducible factors (HIFs), processes that are mainly regulated by the oxygen-and iron-dependent activity of the prolyl hydroxylase domain (PHD) enzymes and that require von Hippel-Lindau tumor suppressor (VHL). 3 VHL encodes four different isoforms (pVHL-213, pVHL-160, pVHL-172, and pVHL-X1). 4 Mutations leading to VHL loss of function result in a number of diseases with divergent features. 5 These diseases include the VHL syndrome, an inherited disorder due to germline VHL alterations that lead to a predisposition to the development, on a somatic second hit, of a variety of tumors and fluid-filled sacs (cysts) in several body regions 6 ; sporadic tumors, such as cerebellar hemangioblastomas, pheochromocytomas, and clear-cell renal-cell carcinoma 7,8 ; and familial erythrocytosis type 2, caused by a biallelic germline VHL mutation (canonically c.598C→T [R200W], causing Chuvash polycythemia) that results in increased expression of HIF target genes. 9 Different sporadic VHL mutations have been reported 10 in addition to the canonical R200W mutation; some of these mutations are as

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…1 a) [ 51 ]. With that in mind, inactivation of VHL, including mutations and other modifications such as methylation, is associated with various illnesses such as clear-cell renal cell carcinoma (ccRCC) due to aberrant VHL/HIF axis and may also affects human phenotypes [ 52 , 53 ]. VHL encodes two RNA (variant 1 and variant 2), three different protein isoforms (pVHL213, pVHL160 and pVHL172).…”

“…More, mutations in mTOR interdict the PI3K-AKT-mTOR pathway, for example, mutations in PTEN lipid phosphatase and the Tuberous Sclerosis Complex 1/2 (TSC1/2) leads to mTOR dysfunction, which resulting in usage of mTOR inhibitors in clinical treatment [ 298 ]. Authentic study noted that VHL-deficient germline resulting in reduced high-density lipoprotein (HDL) cholesterol which is associated with HIF-dependent pathway, and insulin induced gene 2 (INSIG2) is subsequently activated which leads to low levels of fatty acids (FAs) and cholesterol [ 52 ]. Similarly, in tumors with VHL loss, HIF-2α activation promotes lipid droplets accumulation followed by elevated expression of both FAs synthesis and FAs absorption-related genes [ 308 ].…”

The structural basis for intermitochondrial communications is fundamentally different in cardiac and skeletal muscle

“…Fatigue in fast muscle fibres of the mouse is associated with a higher frequency of elongated constrictions within the body of individual mitochondria, and the subsequent development into short connecting ducts (Figure ; Lavorato, Loro, Debattisti, Khurana, & Franzini‐Armstrong, ). Moreover, in a novel, human genetic condition (Perrotta et al., ), unusually thin and elongated mitochondrial tubes have been discovered (Figure ). Levels of the von Hippel–Lindau protein are reduced in this condition, leading to a largely hypoxic phenotype at multiple levels and exposing the mitochondria to metabolic stress.…”

“…Intermitochondrial ducts in the muscle from a patient with a mutation leading to reduced levels of von Hippel–Lindau protein. (a) Mitochondria from a vastus lateralis biopsy of a patient with a mutation leading to reduced von Hippel–Lindau protein levels, associated with an abnormal metabolic phenotype and mitochondrial stress (Perrotta et al., ). The mitochondrial response in this case is an extension of the organelles (a; at arrows), meaning that the wider regions are connected by long, extended tunnels that follow the transversely oriented path occupied by mitochondria (Perrotta et al., ).…”

“…(a) Mitochondria from a vastus lateralis biopsy of a patient with a mutation leading to reduced von Hippel–Lindau protein levels, associated with an abnormal metabolic phenotype and mitochondrial stress (Perrotta et al., ). The mitochondrial response in this case is an extension of the organelles (a; at arrows), meaning that the wider regions are connected by long, extended tunnels that follow the transversely oriented path occupied by mitochondria (Perrotta et al., ). (b) Elongated profiles are patently connected to mitochondria at either end and thus differ from the asymmetric nanotunnels illustrated in Figure .…”