Three-dimensional ultrastructure of giant mitochondria in human non-alcoholic fatty liver disease

Abstract

Giant mitochondria are peculiarly shaped, extremely large mitochondria in hepatic parenchymal cells, the internal structure of which is characterised by atypically arranged cristae, enlarged matrix granules and crystalline inclusions. The presence of giant mitochondria in human tissue biopsies is often linked with cellular adversity, caused by toxins such as alcohol, xenobiotics, anti-cancer drugs, free-radicals, nutritional deficiencies or as a consequence of high fat Western diets. To date, non-alcoholic fatty liver disease is the most prevalent liver disease in lipid dysmetabolism, in which mitochondrial dysfunction plays a crucial role. It is not well understood whether the morphologic characteristics of giant mitochondria are an adaption or caused by such dysfunction. In the present study, we employ a complementary multimodal imaging approach involving array tomography and transmission electron tomography in order to comparatively analyse the structure and morphometric parameters of thousands of normal- and giant mitochondria in four patients diagnosed with non-alcoholic fatty liver disease. In so doing, we reveal functional alterations associated with mitochondrial gigantism and propose a mechanism for their formation based on our ultrastructural findings.

Liver Zonation – Revisiting Old Questions With New Technologies

“…Recent improvements in imaging and mathematical modeling technology have overcome the limitation of 2D imaging of subcellular organelles. Using a combination of array tomography, transmission electron tomography, and 3D modeling technology, the ultrastructure and morphology of giant mitochondria were analyzed in livers from NAFLD patients ( Shami et al, 2021 ). This analysis revealed the decreased surface area to volume ratio and disorganized cristae contribute to the mitochondrial dysfunction during NAFLD development, but unfortunately authors did not make comparisons between zones in the lobule.…”

Opaque Polyploid Cells in Ishikawa Endometrial Cultures Are Capable of Forming Megamitochondria, Organelles Derived from the Adaptation of Fused Mitochondria Whose Capacity to Develop Gaseous Vacuoles Suggests CO<sub>2</sub> Retention and Hypoxic Metabolism

“…A couple of changes worth noticing include the demarcation between the developing structure and surrounding monolayer cells that have been numbered 6, 8, and 9, and a structure like a monolayer cell emerging at position 7. Something that might be similar to crystalline structures observed in developing megamitochondria [25] can be observed in the interior of developing cell #10.…”

“…Hybrid and transient, mitonucleons are formed by the fusion of multiple mitochondria around aggregated nuclei in syncytia [9]. Three or four mitonucleons form within a syncytium, fill with gas, and elevate separately so that, for a short period of time, they create multiple protuberances in an "expanding" syncytial apical membrane that most likely includes endoplasmic reticulum membranes associated with the giant mitochondria, an association observed in tissues such as endometrium [37], in the adrenal cortex [38] and in human hepatocytes [25].…”

“…Recently tomography enabled a complete survey of megamitochondria and normal mitochondria in the livers of deceased patients with non-alcoholic fatty liver disease [25]. Using 4 livers in the study, researchers examined every mitochondrion and concluded that the internal configuration of what they called giant mitochondria "is both multifold and dramatically distinct from their normal-sized counterparts."…”

Fat causes necrosis and inflammation in parenchymal cells in human steatotic liver

“…Array tomography was utilized to generate large cellular volumes at the ultrastructural level as described previously (Moore et al 2020;Shami et al 2021). A series of 350 sections (300 nm thick) was generated and collected on a hydrophilized glass slide.…”