Proteomic Profiling of Adipose Tissue from Zmpste24−/− Mice, a Model of Lipodystrophy and Premature Aging, Reveals Major Changes in Mitochondrial Function and Vimentin Processing

Abstract

Lipodystrophy is a major disease involving severe alterations of adipose tissue distribution and metabolism. Mutations in genes encoding the nuclear envelope protein lamin A or its processing enzyme, the metalloproteinase Zmpste24, cause diverse human progeroid syndromes that are commonly characterized by a selective loss of adipose tissue. Similarly to humans, mice deficient in Zmpste24 accumulate prelamin A and display phenotypic features of accelerated aging, including lipodystrophy. Herein, we report the proteome and phosphoproteome of adipose tissue as well as serum metabolome in lipodystrophy by using Zmpste24 ؊/؊ mice as experimental model. We show that Zmpste24 deficiency enhanced lipolysis, fatty acid biogenesis and ␤-oxidation as well as decreased fatty acid re-esterification, thus pointing to an increased partitioning of fatty acid toward ␤-oxidation and away from storage that likely underlies the observed size reduction of Zmpste24-null adipocytes. Besides the mitochondrial proteins related to lipid metabolism, other protein networks related to mitochondrial function, including those involved in tricarboxylic acid cycle and oxidative phosphorylation, were up-regulated in Zmpste24 ؊/؊ mice. These results, together with the observation of an increased mitochondrial response to oxidative stress, support the relationship between defective prelamin A processing and mitochondrial dysfunction and highlight the relevance of oxidative damage in lipoatrophy and aging. We also show that absence of Zmpste24 profoundly alters the processing of the cytoskeletal protein vimentin and identify a novel protein dysregulated in lipodystrophy, High-Mobility Group Box-1 Protein. Finally, we found several lipid derivates with important roles in energy balance, such as Lysophosphatidylcholine or 2-arachidonoylglycerol, to be dysregulated in Zmpste24

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

“…The phenomenon can be reversed by raising NAD+ levels [340]. Transcription of genes encoding mitochondrial proteins is impaired during laminopathies leading to an imbalance between mitochondrial and nuclear proteins especially those constituting complexes I, III and IV of the respiratory chain and the ATPsynthase [341][342][343]. This imbalance triggers the mitochondrial unfolded protein response (UPRmt) [344], whereby mitochondria send a signal to the nucleus to induce the production of stress-related proteins, which restore the mitochondrial balance.…”

Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy

“…The latter phenomenon is conserved in species from worms to humans and can be rescued by caloric restriction, suggesting it plays an important role in the regulation of longevity. Here, we created 2 mouse models to explore the role of the de- ipose tissue can also lead to accelerated aging and lipodystrophy (63,64). We now find that dicer is downregulated in the adipose tissue of patients with HIV and HIV-related partial lipodystrophy, and these individuals may exhibit signs of premature aging, metabolic syndrome (diabetes and dyslipidemia), cardiovascular disease, and increased sensitivity to stress (38).…”

Oxydative stress alters nuclear shape through lamins dysregulation

“…52 The alteration of mitochondrial metabolism was also suggested by a proteomic analysis of zmpste24 -/-cells. 53 A unifying model can be proposed in which oxidative stress, regardless of the cause, affects lamins proteins functions and/or levels, resulting in both alteration of nuclear envelop structure and in loss of redox control, which amplify the oxidative stress. In agreement with this model, it has recently been reported that the tail domain of lamin A is a target of oxidative damage, and its irreversible oxidation led to a loss of lamin A function and entry into senescence.…”