Phenotypes Associated with This Genotype

Genotype
MGI:7448528

• Allelic Composition: Mfn2^tm3Dcc/Mfn2^tm3Dcc; Tg(Stra8-icre)1Reb/0
• Genetic Background: involves: 129 * C57BL/6J * FVB/NJ

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

reproductive system

abnormal male germ cell morphology ( J:305430 )

♂ • at P42, late-stage spermatocytes and round spermatids appear to gradually vacuolize

♂ • TEM analysis of adult testes showed mitochondrial swelling and fragmentation in male germ cells

decreased male germ cell number ( J:305430 )

♂ • at P42, late-stage spermatocytes and round spermatids are decreased in number

oligozoospermia ( J:305430 )

♂ • adult males show a dramatic reduction in the number of spermatozoa retrieved from the cauda epididymis

increased testis apoptosis ( J:305430 )

♂ • TUNEL assays show a significantly increased number of apoptotic cells in the testes at P35 and P56

♂ • however, testis histology is normal at P7-P28 and no increase in apoptosis is noted at P14 and P28

abnormal male germ cell physiology ( J:305430 )

♂ • male germ cells exhibit increased mitochondrial fission

increased male germ cell apoptosis ( J:305430 )

♂ • from P35, most male germ cells are gradually lost by apoptosis

small seminiferous tubules ( J:305430 )

♂ • as adult males age, the number of severely atrophic seminiferous tubules is increased

seminiferous tubule degeneration ( J:305430 )

♂ • as adult males age, seminiferous tubules become severely atrophic and vacuolated (P60 to P120)

small testis ( J:305430 )

♂ • testes are significantly smaller at P56

decreased testis weight ( J:305430 )

♂ • testis weight/body weight ratio is significantly decreased from P35 to P120

abnormal spermatogenesis ( J:305430 )

♂ • males show age-dependent spermatogenic defects, with germ cells starting to decline after P35

teratozoospermia ( J:305430 )

♂ • only ~2% of epididymal sperm display normal morphology versus ~80% in wild-type controls

coiled sperm flagellum ( J:305430 )

♂ • ~14% of sperm exhibit a coiled tail

abnormal sperm head morphology ( J:305430 )

♂ • ~31% of sperm exhibit a bent head

absent sperm head ( J:305430 )

♂ • ~53% of sperm are acephalic

abnormal spermatid morphology ( J:305430 )

♂ • at P42, round spermatids are decreased in number and appear to gradually vacuolize

♂ • analysis of the mitochondrial aspect ratio (AR) distribution (where AR is ratio of the major axis to the minor axis of mitochondria) showed an increased % of short mitochondria in round spermatids

♂ • the distance between mitochondria and endoplasmic reticulum (ER) is increased by ~16% while the % of mitochondria-ER contacts is reduced by almost 50% and the ER-mitochondria contact coefficient (ERMICC) is reduced by >30% in round spermatids

decreased round spermatid number ( J:305430 )

♂ • at P42

abnormal spermatocyte morphology ( J:305430 )

♂ • at P42, late-stage spermatocytes are decreased in number and appear to gradually vacuolize

♂ • at P60, pachytene spermatocytes show a significantly increased thickness of the inter-mitochondrial cement (IMC)

♂ • at P18, immunostaining of calreticulin -- a mitochondria-associated ER membranes (MAMs) and ER marker protein -- showed a diffused granular pattern in the cytoplasm of spermatocytes instead of the continuous perinuclear localization seen in controls; at P60, calreticulin signals appear to be reduced and show diffused granular distribution

small epididymis ( J:305430 )

♂ • epididymis is significantly smaller at P56

male infertility ( J:305430 )

♂ • all males fail to produce offspring after mating with fertility-proven adult wild-type females for 5 months

cellular

cellular phenotype ( J:305430 )

♂N • immunofluorescent images of ATP5A (an outer mitochondria membrane marker) showed normal mitochondrial distribution in testicular sections at P25

abnormal male germ cell morphology ( J:305430 )

♂ • at P42, late-stage spermatocytes and round spermatids appear to gradually vacuolize

♂ • TEM analysis of adult testes showed mitochondrial swelling and fragmentation in male germ cells

teratozoospermia ( J:305430 )

♂ • only ~2% of epididymal sperm display normal morphology versus ~80% in wild-type controls

coiled sperm flagellum ( J:305430 )

♂ • ~14% of sperm exhibit a coiled tail

abnormal sperm head morphology ( J:305430 )

♂ • ~31% of sperm exhibit a bent head

absent sperm head ( J:305430 )

♂ • ~53% of sperm are acephalic

abnormal spermatid morphology ( J:305430 )

♂ • at P42, round spermatids are decreased in number and appear to gradually vacuolize

♂ • analysis of the mitochondrial aspect ratio (AR) distribution (where AR is ratio of the major axis to the minor axis of mitochondria) showed an increased % of short mitochondria in round spermatids

♂ • the distance between mitochondria and endoplasmic reticulum (ER) is increased by ~16% while the % of mitochondria-ER contacts is reduced by almost 50% and the ER-mitochondria contact coefficient (ERMICC) is reduced by >30% in round spermatids

abnormal spermatocyte morphology ( J:305430 )

♂ • at P42, late-stage spermatocytes are decreased in number and appear to gradually vacuolize

♂ • at P60, pachytene spermatocytes show a significantly increased thickness of the inter-mitochondrial cement (IMC)

♂ • at P18, immunostaining of calreticulin -- a mitochondria-associated ER membranes (MAMs) and ER marker protein -- showed a diffused granular pattern in the cytoplasm of spermatocytes instead of the continuous perinuclear localization seen in controls; at P60, calreticulin signals appear to be reduced and show diffused granular distribution

decreased male germ cell number ( J:305430 )

♂ • at P42, late-stage spermatocytes and round spermatids are decreased in number

oligozoospermia ( J:305430 )

♂ • adult males show a dramatic reduction in the number of spermatozoa retrieved from the cauda epididymis

decreased round spermatid number ( J:305430 )

♂ • at P42

abnormal endoplasmic reticulum morphology ( J:305430 )

♂ • at P60, round spermatids exhibit a fragmented ER structure instead of the tube-like cisternae structures seen in control spermatids

abnormal mitochondrial morphology ( J:305430 )

♂ • TEM analysis of adult testes showed mitochondrial swelling and fragmentation in male germ cells

♂ • at P60, pachytene spermatocytes show a significantly increased thickness of the inter-mitochondrial cement (IMC)

♂ • analysis of the mitochondrial aspect ratio (AR) distribution (where AR is ratio of the major axis to the minor axis of mitochondria) showed an increased % of short mitochondria in round spermatids

♂ • the distance between mitochondria and endoplasmic reticulum (ER) is increased by ~16% while mitochondria-ER contacts are reduced by almost 50% and the ER-mitochondria contact coefficient (ERMICC) is reduced by >30% in round spermatids

♂ • at P18, immunostaining of calreticulin -- a mitochondria-associated ER membranes (MAMs) and ER marker protein -- showed a diffused granular pattern in the cytoplasm of spermatocytes instead of the continuous perinuclear localization seen in controls; at P60, calreticulin signals appear to be reduced and show diffused granular distribution

increased mitochondrial DNA content ( J:305430 )

♂ • adult testes show a significant increase in mitochondrial DNA copy number at P60

increased testis apoptosis ( J:305430 )

♂ • TUNEL assays show a significantly increased number of apoptotic cells in the testes at P35 and P56

♂ • however, testis histology is normal at P7-P28 and no increase in apoptosis is noted at P14 and P28

abnormal mitochondrial ATP synthesis coupled electron transport ( J:305430 )

♂ • cytochrome c oxidase (COX, complex IV) activity is increased in adult testis sections

♂ • in contrast, succinate dehydrogenase (SDH, complex II) activity is normal

abnormal male germ cell physiology ( J:305430 )

♂ • male germ cells exhibit increased mitochondrial fission

increased male germ cell apoptosis ( J:305430 )

♂ • from P35, most male germ cells are gradually lost by apoptosis

increased mitochondrial fission ( J:305430 )

♂ • male germ cells exhibit increased mitochondrial fission

endocrine/exocrine glands

increased testis apoptosis ( J:305430 )

♂ • TUNEL assays show a significantly increased number of apoptotic cells in the testes at P35 and P56

♂ • however, testis histology is normal at P7-P28 and no increase in apoptosis is noted at P14 and P28

small seminiferous tubules ( J:305430 )

♂ • as adult males age, the number of severely atrophic seminiferous tubules is increased

seminiferous tubule degeneration ( J:305430 )

♂ • as adult males age, seminiferous tubules become severely atrophic and vacuolated (P60 to P120)

small testis ( J:305430 )

♂ • testes are significantly smaller at P56

decreased testis weight ( J:305430 )

♂ • testis weight/body weight ratio is significantly decreased from P35 to P120