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Review
. 2017 Apr;42(4):312-325.
doi: 10.1016/j.tibs.2017.01.003. Epub 2017 Feb 7.

Mitochondrial Complex II: At the Crossroads

Ayenachew Bezawork-Geleta  1 , Jakub Rohlena  2 , Lanfeng Dong  3 , Karel Pacak  4 , Jiri Neuzil  5
Affiliations
Review

Mitochondrial Complex II: At the Crossroads

Ayenachew Bezawork-Geleta et al. Trends Biochem Sci. 2017 Apr.

Abstract

Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited.

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Figures

Figure 1.
Figure 1.. Crystal Structure of Succinate Dehydrogenase (SDH) Isolated from Porcine Heart Mitochondria and its Three Prosthetic Groups.
(A) shows subunits of SDH: SDHA (blue), SDHB (green), SDHC (brown), and SDHD (red). (B) highlights three prosthetic groups of SDH. For details see [2] (PDB:1ZOY).
Figure 2.
Figure 2.. Step-Wise Assembly of Succinate Dehydrogenase (SDH) and the Putative Role of the Protease LON in the Degradation of SDHAF1 and SDHAF2/SDH5.
Flavination of SDHA requires SDH5/SDHAF2 and other putative factors. Following flavination, the chaperone-like assembly factor SDHAF4 binds to SDHA to reduce auto-oxidation. The insertion of [Fe–S] clusters into SDHB requires the assembly factor SDHAF1 and later SDHAF3 to protect the system from oxidative damage. SDHAF3 also facilitates the formation of a transitional SDHA–SDHB subcomplex. The assembly of the SDHC and SDHD subunits and heme to form the holoenyme is depicted. The detailed mechanism of this process remains to be discovered.
Figure 3.
Figure 3.. Post-translational Modifications of Succinate Dehydrogenase (SDH) Subunits that Affect the Activity of the Complex.
Phosphorylation, deacetylation, and succinylation are shown to increase the activity of SDH while the reverse modifications reduce its enzymatic activity.
Figure 4.
Figure 4.. Succinate Dehydrogenase (SDH) as a Target for Anticancer Agents.
(A) The scheme documents the position of α-tocpheryl succinate (α-TOS) within the SDHC subunit, including its hydrogen bonding to the ubiquinone (UbQ)-binding Ser42 residue of the SDHC subunit. Adapted from [92]. (B) The scheme indicates the subunits of complex II (CII) and its SDH and SQR activities lined to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). α-TOS acts by interfering with the UbQ-binding site, resulting in ROS generation and, in turn, induction of apoptosis.
See this image and copyright information in PMC

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