Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury

Abstract

Porphyrias are caused by pathological accumulation of porphyrins and their precursors, with liver damage and cancer risk, photosensitivity, and neurovisceral involvement. Fluorescent porphyrins bind proteins reversibly and lead, in the presence of oxygen, to protein oxidation and aggregation with consequent cellular damage. Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, lightinduced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.

Oxidative stress in human facial skin observed by ultraweak photon emission imaging and its correlation with biophysical properties of skin

“…However, UPE detection may be useful to determine the levels of porphyrins without using UV radiation indirectly. Furthermore, porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage 35 . Therefore, UPE-based detection methods can improve our understanding of porphyrin-related disorders.…”

Clinical Guide and Update on Porphyrias

“…12 The lipophilic PPIX, which is eliminated via bile, is hepatotoxic at high concentrations, causing varying degrees of liver damage. [107][108][109] Protoporphyrin-containing crystals can be detected as pathognomonic Maltese crosses upon histologic examination of liver sections under polarized light ( Figure 2F). 110 As many as 23% of patients with EPP develop protoporphyrin-containing gallstones that emit red fluorescence under long-wave ultraviolet light.…”

“…In a small proportion of patients, the cutaneous symptoms are associated with abdominal pain, about one-quarter display abnormal liver enzyme activities and rarely develop severe hepatobiliary injury, including jaundice and liver cirrhosis, can occur. 108,111 Therefore, EPP or XLP should be considered for cases of unexplained cholestasis, and physicians should ask patients if they are photosensitive because patients often do not report this spontaneously. Finally, patients often present with iron deficiency and corresponding microcytic anemia.…”

Models for human porphyrias: Have animals in the wild been overlooked?

“…[13] This injury is exerted by the porphyrin-mediated with the oxidized proteins to form protein aggregates, which impair organelles and inhibit the proteasome. [14] This light-independent mechanism of toxicity adds to a lightdependent mechanism when the accumulated porphyrins are transferred from the circulatory system to the skin, where porphyrins exert phototoxicity. [4] This is because the chemical structure of porphyrins ( Figure 2) makes them prone to photo destruction when exposed to visible light.…”

“…Porphyrins subsequently interact with the oxidized proteins to form protein aggregates, which impair organelles and inhibit the proteasome. [ 14 ]…”