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Mitoflash altered by metabolic stress in insulin-resistant skeletal muscle.

Ding Y, Fang H, Shang W, Xiao Y, Sun T, Hou N, Pan L, Sun X, Ma Q, Zhou J, Wang X, Zhang X, Cheng H - J. Mol. Med. (2015)

Bottom Line: In conjunction with in vivo imaging of skeletal muscles, we uncovered a progressive increase of mitoflash frequency along with its morphological changes.Interestingly, enhanced mitochondrial networking occurred at 12 weeks of age, and this was followed by mitochondrial fragmentation at 34 weeks.Mechanistic study revealed that the mitoflash remodeling was associated with altered expression of proteins involved in mitochondrial dynamics and quality control.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.

ABSTRACT

Unlabelled: Central to bioenergetics and reactive oxygen species (ROS) signaling, the mitochondrion plays pivotal roles in the pathogenesis of metabolic diseases. Recent advances have shown that mitochondrial flash ("mitoflash") visualized by the biosensor mt-cpYFP affords a frequency-coded, optical readout linked to mitochondrial ROS production and energy metabolism, at the resolution of a single mitochondrion. To investigate possible mitoflash responses to metabolic stress in insulin resistance (IR), we generated an mt-cpYFP-expressing db/db mouse model with the obesity and IR phenotypes unaltered. In conjunction with in vivo imaging of skeletal muscles, we uncovered a progressive increase of mitoflash frequency along with its morphological changes. Interestingly, enhanced mitochondrial networking occurred at 12 weeks of age, and this was followed by mitochondrial fragmentation at 34 weeks. Pioglitazone treatment normalized mitoflash frequency and morphology while restored mitochondrial respiratory function and insulin sensitivity in 12 weeks mt-cpYFP db/db mice. Mechanistic study revealed that the mitoflash remodeling was associated with altered expression of proteins involved in mitochondrial dynamics and quality control. These findings indicate that mitoflash activity may serve as an optical functional readout of the mitochondria, a robust and sensitive biomarker to gauge IR stresses and their amelioration by therapeutic interventions.

Key message: • In vivo detection of mitochondrial flashes in mt-cpYFP-expressing db/db mouse. • Mitoflash frequency increased progressively with disease development. • Mitoflash morphology revealed a biphasic change in mitochondrial networking. • Mitoflash abnormalities and mitochondrial defects are restored by pioglitazone. • Mitoflash may serve as a unique biomarker to gauge metabolic stress in insulin resistance.

No MeSH data available.


Related in: MedlinePlus

TEM micrographs of mitochondrial networking changes in IR skeletal muscle. Representative TEM micrographs in (a) and (c) show altered mitochondrial morphology and networking in skeletal muscles of 12- and 34-week-old mt-cpYFP db/db mice compared to mt-cpYFP db/m littermates. Left, ×12,000; right, ×40,000. Statistics of perimeters of mitochondria in TEM micrographs in (b) and (d) show enlargement and enhanced connectivity at 12 weeks followed by fragmentation at 34 weeks (n = 4 mice for each group). Data are expressed as mean ± SEM. ***p < 0.001 vs age-matched mt-cpYFP db/m mice; values were subject to Student’s t test
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Fig4: TEM micrographs of mitochondrial networking changes in IR skeletal muscle. Representative TEM micrographs in (a) and (c) show altered mitochondrial morphology and networking in skeletal muscles of 12- and 34-week-old mt-cpYFP db/db mice compared to mt-cpYFP db/m littermates. Left, ×12,000; right, ×40,000. Statistics of perimeters of mitochondria in TEM micrographs in (b) and (d) show enlargement and enhanced connectivity at 12 weeks followed by fragmentation at 34 weeks (n = 4 mice for each group). Data are expressed as mean ± SEM. ***p < 0.001 vs age-matched mt-cpYFP db/m mice; values were subject to Student’s t test

Mentions: To determine the structural basis underlying this biphasic change of mitoflash morphology during disease development, we next used TEM to complement the optical fluorescent imaging approach. In control mice at 12 weeks, most mitochondria were spheroid or bean shaped and appeared at the dyads of Z-lines. A small proportion of elongated tubular mitochondria were also observed. In mt-cpYFP db/db mice, congruent with increased communal mitoflash activity and area, more elongated tubular and irregularly shaped mitochondria with an increased perimeter were seen (Fig. 4a, b).Fig. 4


Mitoflash altered by metabolic stress in insulin-resistant skeletal muscle.

Ding Y, Fang H, Shang W, Xiao Y, Sun T, Hou N, Pan L, Sun X, Ma Q, Zhou J, Wang X, Zhang X, Cheng H - J. Mol. Med. (2015)

TEM micrographs of mitochondrial networking changes in IR skeletal muscle. Representative TEM micrographs in (a) and (c) show altered mitochondrial morphology and networking in skeletal muscles of 12- and 34-week-old mt-cpYFP db/db mice compared to mt-cpYFP db/m littermates. Left, ×12,000; right, ×40,000. Statistics of perimeters of mitochondria in TEM micrographs in (b) and (d) show enlargement and enhanced connectivity at 12 weeks followed by fragmentation at 34 weeks (n = 4 mice for each group). Data are expressed as mean ± SEM. ***p < 0.001 vs age-matched mt-cpYFP db/m mice; values were subject to Student’s t test
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4589561&req=5

Fig4: TEM micrographs of mitochondrial networking changes in IR skeletal muscle. Representative TEM micrographs in (a) and (c) show altered mitochondrial morphology and networking in skeletal muscles of 12- and 34-week-old mt-cpYFP db/db mice compared to mt-cpYFP db/m littermates. Left, ×12,000; right, ×40,000. Statistics of perimeters of mitochondria in TEM micrographs in (b) and (d) show enlargement and enhanced connectivity at 12 weeks followed by fragmentation at 34 weeks (n = 4 mice for each group). Data are expressed as mean ± SEM. ***p < 0.001 vs age-matched mt-cpYFP db/m mice; values were subject to Student’s t test
Mentions: To determine the structural basis underlying this biphasic change of mitoflash morphology during disease development, we next used TEM to complement the optical fluorescent imaging approach. In control mice at 12 weeks, most mitochondria were spheroid or bean shaped and appeared at the dyads of Z-lines. A small proportion of elongated tubular mitochondria were also observed. In mt-cpYFP db/db mice, congruent with increased communal mitoflash activity and area, more elongated tubular and irregularly shaped mitochondria with an increased perimeter were seen (Fig. 4a, b).Fig. 4

Bottom Line: In conjunction with in vivo imaging of skeletal muscles, we uncovered a progressive increase of mitoflash frequency along with its morphological changes.Interestingly, enhanced mitochondrial networking occurred at 12 weeks of age, and this was followed by mitochondrial fragmentation at 34 weeks.Mechanistic study revealed that the mitoflash remodeling was associated with altered expression of proteins involved in mitochondrial dynamics and quality control.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.

ABSTRACT

Unlabelled: Central to bioenergetics and reactive oxygen species (ROS) signaling, the mitochondrion plays pivotal roles in the pathogenesis of metabolic diseases. Recent advances have shown that mitochondrial flash ("mitoflash") visualized by the biosensor mt-cpYFP affords a frequency-coded, optical readout linked to mitochondrial ROS production and energy metabolism, at the resolution of a single mitochondrion. To investigate possible mitoflash responses to metabolic stress in insulin resistance (IR), we generated an mt-cpYFP-expressing db/db mouse model with the obesity and IR phenotypes unaltered. In conjunction with in vivo imaging of skeletal muscles, we uncovered a progressive increase of mitoflash frequency along with its morphological changes. Interestingly, enhanced mitochondrial networking occurred at 12 weeks of age, and this was followed by mitochondrial fragmentation at 34 weeks. Pioglitazone treatment normalized mitoflash frequency and morphology while restored mitochondrial respiratory function and insulin sensitivity in 12 weeks mt-cpYFP db/db mice. Mechanistic study revealed that the mitoflash remodeling was associated with altered expression of proteins involved in mitochondrial dynamics and quality control. These findings indicate that mitoflash activity may serve as an optical functional readout of the mitochondria, a robust and sensitive biomarker to gauge IR stresses and their amelioration by therapeutic interventions.

Key message: • In vivo detection of mitochondrial flashes in mt-cpYFP-expressing db/db mouse. • Mitoflash frequency increased progressively with disease development. • Mitoflash morphology revealed a biphasic change in mitochondrial networking. • Mitoflash abnormalities and mitochondrial defects are restored by pioglitazone. • Mitoflash may serve as a unique biomarker to gauge metabolic stress in insulin resistance.

No MeSH data available.


Related in: MedlinePlus