Abstract
Mitochondrial dysfunction is a feature of type I and type II diabetes, but there is a lack of consistency between reports and links to disease development. We aimed to investigate if mitochondrial structure–function remodelling occurs in the early stages of diabetes by employing a mouse model (GENA348) of Maturity Onset Diabetes in the Young, exhibiting hyperglycemia, but not hyperinsulinemia, with mild left ventricular dysfunction. Employing 3-D electron microscopy (SBF-SEM) we determined that compared to wild-type, WT, the GENA348 subsarcolemma mitochondria (SSM) are ~ 2-fold larger, consistent with up-regulation of fusion proteins Mfn1, Mfn2 and Opa1. Further, in comparison, GENA348 mitochondria are more irregular in shape, have more tubular projections with SSM projections being longer and wider. Mitochondrial density is also increased in the GENA348 myocardium consistent with up-regulation of PGC1-α and stalled mitophagy (down-regulation of PINK1, Parkin and Miro1). GENA348 mitochondria have more irregular cristae arrangements but cristae dimensions and density are similar to WT. GENA348 Complex activity (I, II, IV, V) activity is decreased but the OCR is increased, potentially linked to a shift towards fatty acid oxidation due to impaired glycolysis. These novel data reveal that dysregulated mitochondrial morphology, dynamics and function develop in the early stages of diabetes.
Highlights
Mitochondrial dysfunction is a feature of type I and type II diabetes, but there is a lack of consistency between reports and links to disease development
We have identified: (1) Morphological changes to the gross shape of the GENA348 mitochondrial subpopulations and (2) that there are more GENA348 mitochondria with tubular projections, with subsarcolemma mitochondria (SSM) having longer and wider tubules than in WT. (3) There is an increase in overall mitochondrial density and (4) increase to SSM size and relative mitochondrial density within the GENA348 cardiomyocytes
(5) GENA348 mitochondria have aberrant Complex activity and oxygen consumption rates (OCR) compared to WT mitochondria
Summary
Mitochondrial dysfunction is a feature of type I and type II diabetes, but there is a lack of consistency between reports and links to disease development. GENA348 Complex activity (I, II, IV, V) activity is decreased but the OCR is increased, potentially linked to a shift towards fatty acid oxidation due to impaired glycolysis These novel data reveal that dysregulated mitochondrial morphology, dynamics and function develop in the early stages of diabetes. As reviewed by Forte et al.[5] there are multiple reports of expression level changes to proteins mediating mitochondrial dynamics across a range of cardiovascular disorders with strategies to promote fusion, or inhibit fission, having suggested therapeutic applications. Unlike non-muscle cells, cardiac mitochondria can be grouped into spatially distinct populations; subsarcolemmal mitochondria (SSM), interfibrillar mitochondria (IFM) and perinuclear mitochondria (PNM) Studies suggest that these populations are functionally heterogeneous for example, IFM are associated with increased respiration rates for driving neighbouring sarcomeric c ontraction[11,12]. There are reports of mitochondrial subpopulations being differentially affected by pathological stress with the SSM linked to higher levels of ROS generation13. 3-D electron microscopy methods have revealed that the SSM, IFM and PNM form a complex inter-connected network throughout the cardiomyocyte; the formation of a mitochondrial continuum does not necessarily negate spatially organised mitochondria having differing roles or varying stress r esponses[14]
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