Building the batteries of cells

August 11, 2020

Mitochondria are the powerhouse of cells which continuously convert energy from food into the chemical energy currency called ATP. This essential process depends on large protein complexes within the inner membrane of mitochondria acting similar to batteries. A new study, led by Dr. Ruchika Anand and Prof. Andreas Reichert, Heinrich-Heine-University Duesseldorf, Institute of Biochemistry and Molecular Biology I, now found that two lipid-binding proteins located inside of mitochondria control the overall stability of these batteries. This was further shown to be linked to a unique mitochondrial lipid and its synthesis: cardiolipin. Increased build-up of a sugar-modified form of MIC26 was earlier found in blood plasma of the patients suffering from diabetic cardiomyopathy. This study provides the first link between mitochondrial structure, lipids and assembly of large respiratory protein units of mitochondria and their importance in diabetes and heart diseases.

Fat- or lipid-binding proteins called apolipoproteins are well known to bind to lipids (e.g. phospholipids and cholesterol) and to mediate formation of lipoproteins (e.g. HDL or LDL). The main function of lipoproteins is to help to transport lipids in the blood. They take part in uptake, clearance and distribution of all lipids in an organism. Several classes of these proteins are found with different functions. Surprisingly, two apolipoproteins (Apolipoprotein O (APOO/MIC26) and Apolipoprotein O-like (APOOL/MIC27) were earlier found at a location distinct from the blood, namely in mitochondria and associated with a large protein assembly called the MICOS complex. Apolipoprotein O (MIC26) occurs in two forms, a sugar-bound and a non-sugar bound form. While the non-sugar bound form is present inside the mitochondria, the sugar-bound form is found in the blood plasma. Increased quantity of the sugar-bound form in blood plasma was interestingly associated with diabetes and diabetic cardiomyopathy. A mutation in APOO/MIC26 is associated to mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features.

The research groups of Dr. Ruchika Anand and Prof. Dr. Andreas Reichert from the Institute of Biochemistry and Molecular Biology I of the Medical faculty at the HHU in collaboration with scientists Dr. Ilka Wittig from the Goethe University Frankfurt am Main, Germany, and Dr. Thomas Eichmann from the University of Graz, Austria determined the function of these apolipoproteins. They found that the cooperation of the two apolipoproteins of mitochondria (APOO/MIC26 and APOOL/MIC27) are required for the global stability of major mitochondrial protein complexes involved in energy conversion by oxidative phosphorylation. These mitochondrial complexes are arranged in large assemblies so that they can work properly and efficiently to convert the energy from the food into the chemical energy in the form of ATP. The internal structure of mitochondria is arranged and sculptured to accommodate these batteries in the folds of the inner membrane called cristae. APOO/MIC26 and APOOL/MIC27 cooperate to form proper mitochondrial structure including tubular structures located at the entry point of cristae termed crista junctions. The study revealed that both proteins are required together to maintain the correct levels of the mitochondrial specific lipid cardiolipin. The aforementioned scientists found that simultaneous deletion of APOO/MIC26 and APOOL/MIC27 in a cell cause major disturbances in cellular respiration together with occurrence of abnormal mitochondrial structure. This study exemplifies the importance of mitochondrial membrane structures and large protein assemblies in diseases such as diabetic cardiomyopathy and mitochondrial myopathy. This could help to gain further insights for future therapies. The work was published after peer review in Life Science Alliance on August 11th, 2020.
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Heinrich-Heine University Duesseldorf

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